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7252019 Thyroid Receptors
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TRa receptor mutations extend the spectrumof syndromes of reduced sensitivity tothyroid hormone
Virginie
Vlaeminck-Guillem 12 Steacutephanie
Espiard 3
Freacutedeacuteric
Flamant 4
Jean-Louis
Weacutemeau 3
1 Hospices civils de Lyon centre hospitalier Lyon Sud service de biochimiebiologie moleacuteculaire Sud chemin du Grand-Revoyet 69495 Pierre-Beacutenite France
2 Universiteacute Lyon 1 faculteacute de meacutedecine Lyon Est centre Leacuteon-Beacuterard centre derecherche en canceacuterologie de Lyon Inserm 1052 CNRS 5286 69373 Lyon cedex08 France
3 CHRU de Lille hocircpital Huriez service dendocrinologie et meacutetabolisme 59000Lille France
4 Universiteacute de Lyon CNRS Inra universiteacute Claude-Bernard Lyon 1 Eacutecole normalesupeacuterieure de Lyon Institut de geacutenomique fonctionnelle de Lyon 69007 LyonFrance
CorrespondenceVirginie Vlaeminck-Guillem Hospices civils de Lyon centre hospitalier Lyon Sudservice de biochimie biologie moleacuteculaire Sud chemin du Grand-Revoyet69495 Pierre-Beacutenite Francevirginievlaeminck-guillemuniv-lyon1fr
Available online 12 November 2015
Summary
Since 2012 eight different abnormalities have been described in the
THRA gene (encoding the TRa1
thyroid
hormone
receptor) of
14
patients
from
9
families
These
mutations
induce a
clinicalphenotype (resistance to thyroid hormone type a) associating symptoms of untreated mild con-genital
hypothyroidism
and
a
near-normal
range of
free
and
total
thyroid
hormones
and
TSH
(the
T4T3 ratio is nevertheless usually low) The phenotype can diversely include short stature (due togrowth retardation) dysmorphic syndrome (face and limb extremities) psychoneuromotor disor-ders
constipation
and
bradycardia
The
identified
genetic
abnormalities
are
located
within
theligand-binding domain and result in defective T3 binding an abnormally strong interaction withcorepressors
and
a
dominant
negative
activity
against
still
functional
receptors
The
identification
ofpatients
with
consistent
phenotypes
and
the
underlying
mutations
are
warranted
to
better
delineatethe
spectrum
of
the
syndromes
of
reduced
sensitivity
to
thyroid
hormone
Reacutesumeacute
Les
mutations
du
reacutecepteur
TRalpha
eacutetendent
le
spectre
des
syndromes
de
sensibiliteacute
reacuteduite
aux
hormones
thyroiumldiennes
Depuis
2012
huit
anomalies
diffeacuterentes
du
gegravene
THRA qui
code
le
reacutecepteur
TR a1 des
hormones
thyroiumldiennes
ont
eacuteteacute
rapporteacutees
chez
14
patients
reacutepartis
dans
9
familles
Elles
induisent
un
pheacutenotype (forme a de la reacutesistance aux hormones thyroiumldiennes) associant des signes eacutevoquant
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en
ligne
sur
on
line
onwwwem-consultecomrevuelpmwwwsciencedirectcom
ENDOCRINOLOGIE
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IntroductionThe syndromes of reduced sensitivity to thyroid hormone (TH)[1]
were
long
limited
only
to
resistance
to
thyroid
hormone(RTH) due to an abnormality of the beta form of the thyroidhormone receptor (TRb) with the first clinical description occur-
ring
in
1967
[2]
and
the
first
demonstration
of
the
underlyingmolecular mechanism in 1989 [3] The secondary description oftypical
sporadic
and
familial
cases
though
without
identifiedabnormality of the
THRB (thyroid hormone receptor beta) gene
(currently
estimated
at
about
15
of
cases)
quickly
suggestedthe possibility of other molecular causes for the lack of tissuesensitivity to the action of TH [4ndash6] It was not until the mid-2000s
that
abnormalities
in
transmembrane
transport
and
THmetabolism were described as the cause of this reduced sensi-tivity
of
target
tissues
to
TH
action
affecting
respectively
theMCT8 gene (monocarboxylate transporter 8) and the SBP2 gene(selenocysteine
insertion
sequence-binding
protein
2)
[7ndash10]The responsibility of the
THRA (thyroid hormone receptor alpha)
gene which encodes the other functional TH receptor (TRa1)had
been
suggested
but
could
not
be
demonstrated
Whileviable murine models (review in [11]) of inactivation [12] ormutation
[13]
in
the
THRA
gene
have
rapidly
been
publishedmutations in humans were considered by the simple reason oftheir absence to be extremely rare lethal or subclinicallyexpressed The phenotype of patients in whom
THRA gene
mutations
were
finally
described
is
retrospectively
suggestiveof
that
described
over
10
years
previously
in
murine
models
It
isremarkable however to notice that the first case of RTH due toTRa
abnormality
(named
RTHa in
contrast
with
RTHb
[10])recognized as a state of hypothyroidism with normal thyroid
function
test
was
not
identified
in
2012
through
direct
targetingbut
during
whole
genome
sequencing
[14]
Likewise
the
twoother
cases
described
in
the
same
year
were
discovered
througha
candidate
gene
approach
after
ruling
out
an
abnormalityaffecting a TH transporter or deiodinase [15] Patients indeedpresent
with
quite
normal
thyroid
laboratory
testing
a
confus-ing situation that usually lead patients to present themselves innon-endocrinological clinical departmentsThe
molecular
decoding
of
RTHa has
only
just
begun
and
thedescription of at least several tens of cases will be able to
precisely delineate its clinical spectrum At present only14
patients
with
RTHa
have
been
found
in
the
literatureamongst 9 distinct families [14ndash21] And although their commonclinical aspects are emerging the analysis also clearly showsdiversity
in
the
phenotype
The
purpose
of
this
review
is
topresent published cases of RTHa and to provide details on theirunderlying
molecular mechanisms particularly in the light ofavailable
murine
models
The
objective
is
to
thus
promote
thediagnostic
identification
of
patients
in
order
to
better
define
theextent of the clinical manifestations related to congenital anom-alies of TH action
Clinical presentation and biologyAlthough
14
patients
with
identified
genetic
abnormalities
havebeen reported in the literature clinical data for only 13 of themare
available
The
genetic
identification
for
the
fourteenth
wasdone as part of whole genome sequencing in subjects withfamilial forms of autism [19] Abnormality of the
THRA gene was
not specifically investigated and no description of the case wasavailable
other
than
the
fact
that
the
female
patient
who
wasautistic had a brother who was also an autistic non-carrier of theTHRA
mutation [19]The patients included 9 women and 5 menbut
it
is
too
early
to
define
a
sex
ratio
(it
is
11
in
RTHb [1])
Thecases were sporadic (de novo mutation) or familial (mutationtransmitted by a parent who was a carrier) In the reportedcases
the
age
at
the
molecular
diagnosis
varied
(seven
childrenor adolescents and seven adults) which contributes to certainvariations in the clinical descriptions and even in the adultsuncertainty as to the description of the phenotype in childhoodThe
clinical
presentation
of
RTHa
always
includes
although
to
varying
degrees
the
combination
of
a
dysmorphic
syndromeand psychomotor development disorders (table
I ) Of note is theabsence
of
goiter
which
is
usually
among
the
typical
manifes-tations of RTHb Generally there are signs of mild to moderateuntreated
congenital
hypothyroidism
The
near-normal
valuesof the laboratory thyroid function tests (cf below) must thensignal
the
possibility
of
RTHa
and
prompt
a
genetic
analysis
ofthe patient The manifestations related to hypothyroidism thusreported are mild to moderate intellectual deficit decreasedstature
alterations
in
ossification
macroglossia
and
chronic
une
hypothyroiumldie
congeacutenitale
modeacutereacutee
non
traiteacutee
et
une
(quasi-)
normaliteacute
des
formes
libres
et
totales
des
hormones
thyroiumldiennes
et
de
la
TSH
(le
ratio
T4T3
est
toutefois
habituellement
diminueacute) Le pheacutenotype peut inclure agrave des degreacutes divers une courte taille (par retard de
croissance)
un
syndrome
dysmorphique
(face
et
extreacutemiteacutes
des
membres)
des
troubles
neuro-psychomoteurs
une
constipation
et
une
bradycardie
Les
anomalies
geacuteneacutetiques
ont
eacuteteacute
identi 1047297 eacutees dans le domaine de liaison du ligand et aboutissent agrave un deacutefaut de liaison de la T3 uneinteraction
anormalement
forte
avec
les
coreacutepresseurs
et
une
activiteacute
dominante
neacutegative
sur
les
reacutecepteurs
resteacutes
fonctionnels
La
reconnaissance
des
cas
et
lidenti 1047297 cation
des
mutations
sous-
jacentes
sont
indispensables
pour
mieux
deacute1047297 nir le
spectre
des
syndromes
de
sensibiliteacute
reacuteduite
aux hormones thyroiumldiennes
V Vlaeminck-Guillem S Espiard F Flamant J-LWeacutemeau
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constipation
The
dysmorphic
syndrome
combines
small
staturedecreased
limb
length
with
a
trunk
that
is
of
rather
normal
size(even elongated in the thoracic portion) and multiple facialanomalies
that
may
include
macrocephaly
(the
need
for
acaesarean section was reported several times) rather coarsefeatures hypertelorism of the eyeballs a short and wide nosemicrognathism
delayed
tooth
eruption
a
short
neck
or
evenmacroglossia The decreased stature is related to growth retar-dation
(sometimes
detected
in
utero)
and
can
even
border
ondwarfism [21] The feet and hands may be enlarged
Malformations
have
also
been
reported
such
as
congenitalhip
dislocation
or
coxa
valga
One
described
case
included
aunique malformation syndrome (sufficiently significant to pro-voke
a
separate
publication
more
than
10
years
before
thediscovery of the molecular substratum [22]) with bilateralagenesis of the clavicles unilateral humero-radial synostosiselbow
dislocation
syndactyly
of
the
4th
and
5th
toes
absence
ofthe 12th rib scoliosis and hip dysplasia [21] (presentationsuggestive
of
cleidocranial
dysostosis
[2324]) With
regard
topsychomotor status there have been reports of abnormalities in
TABLE IClinical
phenotype
of
the
14
published
cases
of
resistance
to
thyroid
hormone
due
to
a
defective
TRa
receptor
Gender Females n = 9Males n = 5
Age at the molecular diagnosis Childrenteenagers 6 to 18 years (n = 7)Adults 25 to 60 years (n = 7)
Origin European Caucasian n = 13North-American n = 1
Dysmorphic syndrome
Figure
Growth retardation n = 10Height Small in 9 patients Normal in 3 patients
Weight Thinness n = 1Ideal weight n = 3
Overweight n = 1Obesity n = 3
Long thorax n = 6Short limbs n = 7 No in 3 other patients
Face dysmorphism
Macrocephaly n = 11Coarse facial features n = 6 (no in a
7th patient)
Eye hypertelorism n = 7Flat nasal bridge upturned nose n = 8Short neck n = 4 (no in a 5th patient)
Micrognathia n = 2Macroglossia n = 5 (no in a 6th patient)
Delayed tooth eruption n = 2Malformations n = 5Ends of the limbs n = 3 (congenital dislocation coxa valga)Hip n = 1Cleidocranial dysplasia n = 5
Cognition disorders
Psychomotor disorders Yes n = 7
No n = 7Cognitive defect No defect n = 2
Mild defect n = 7Moderate to severe defect n = 4
Bradycardia n = 5 (no in 3 other patients)
Constipation n = 11 (no in a 12th patient)
Hypercholesterolemia n = 11 (no in a 12th patient)
Anemia Microcytic n = 10Macrocytic n = 3
TRa receptor mutations extend the spectrum of syndromes of reduced sensitivity tothyroid hormone ENDOCRINOLOGIE
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coordination learning to walk and reading Mild to severeintellectual
deficit
has
often
been
reported
but
is
not
systematic[2021] Constipation is nearly constant with an early appear-ance
in
childhood
one
case
of
diarrhoea
occurring
late
inadulthood was described [21] Bradycardia another sign sug-
gestive of hypothyroidism is sometimes reported [141617]Overweight is also possible particularly in adults [15ndash18] Bodytemperature
appears
normal
[1518] whereas
the
baselinemetabolism
is
decreased
[14161721] Finally
cases
of
carpaltunnel syndrome have been reported [17] as is sometimesdescribed
in
association
with
myxoedema
of
hypothyroidismThe routine laboratory tests are normal except for anaemiawhich
is
consistently
present
in
all
clinical
descriptions
but
israther moderate It is usually normocytic though sometimesmacrocytic
[1721]) Hypercholesterolemia
may
also
occur[15ndash1820] Insulin-like
growth
factor
1
may
be
low
in
childrenand adolescents patients [14ndash1618]
Radiological
exams
are
done
to
investigate
potential
malforma-tion syndromes [2021] Skull X-rays in children confirm macro-cephaly and show delay of ossification in the fontanels and thepersistence of wormian bones (which reflect ossification abnor-malities)
[14]
Ossification
delay
is
also
evidenced
by
epiphysealdysgenesis
(femoral
heads)
[141518]
and
by
delayed
boneage An ovoid appearance of the vertebrae is possible [20] Inadults
X-rays
again
show
macrocephaly
with
thickening
of
theskull vault (occipital in particular) and enlargement of the frontalbone [1617] Cortical bone thickening has also been describedon
the
long
bones
of
the
limbs
[16] Osteodensitometric
meas-urements
in
adults
are
usually
normal
[16ndash1821]The signs of hypothyroidism that are typically found lead logi-cally to an investigation of thyroid function tests Though pro-viding
reassurance
when
values
are
normal
or
low
normal
they
must attract attention when there is a discrepancy with the
clinical
presentation
It
is
this
dissociation
between
normallaboratory values and the more or less pronounced signs ofhypothyroidism
(including
the
dysmorphic
syndrome)
thatshould suggest the diagnosis of RTHa It is the opposite condi-
tion of RTHb where the symptoms of hyperthyroidism are ratherminimal in association with laboratory indications of hyperthy-roidism
(table
II )
In
this
respect
it
can
be
seen
that
thedissociation
between
the
clinical
and
laboratory
observationsis a key element of RTH both in the alpha and the beta formsThe
thyroid
hormone
values
both
in
their
free
and
total
formsare more or less normal There is a tendency however for T4 tobe
slightly
low
and
T3
slightly
high
As
a
result
there
is
adecreased T4T3 ratio which was the only consistent factorin
all
the
published
cases
The
TSH
is
normal
(though
low
insome
cases)
It
should
be
noted
that
neonatal
screening
forhypothyroidism which is based on TSH cannot identify RTHa
Several
patients
received
treatment
with
levothyroxine
some-times even before the clinical or specific molecular diagnosisThe clinical effects are inconclusive particularly because cogni-tive disorders and dysmorphic syndrome are often alreadyestablished
and
definitive
[14] Benefits
can
be
seen
for
brady-cardia
energy
levels
bowel
function
and
carpal
tunnel
syn-drome [1617] There is usually an increase in the concentrationsof
thyroid
hormones
and
a
quick
and
predictable
suppression
ofTSH which reflects the successful adaptation of the hypotha-lamic-pituitary axis Improvement of the other abnormal labo-ratory
values
(blood
cholesterol
anaemia)
is
not
constant
Molecular bases of RTHa
The functional thyroid receptors are the isoforms TRb1 TRb2andTRa1 They are present in the nucleus of the target cells as
TABLE IIClinical
and
biological
phenotypes
of
the
a
and
b
syndromes
of
resistance
to
thyroid
hormones
RTHa RTHb
Involved gene THRA THRB
Involved receptors TRa11 TRb1TRb2
Clinical phenotype Mild hypothyroidism(short height dysmorphic syndrom)
Mild hyperthyroidism (tachycardia nervousness)
Goiter No Yes
fT3 High-normal High
fT4 Low normal High
T4T3 ratio Low Low
TSH Normal or low High
1Some mutations of the THRA gene also involve non-functional isoforms such as the TRa2 protein
V Vlaeminck-Guillem S Espiard F Flamant J-LWeacutemeau
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dimers They are capable of binding on theDNA specific targetsequences (thyroid
hormone response elements
or
TREs)which are located in the regulatory sequences (promotersenhancers) of
the target
genes Like the other
nuclear
recep-tors they in fact behave like ligand-inducible transcription
factors In the absence of hormones and through interactionwith cofactors that repress their transcriptional activity (core-pressors) the
TR reduces
the expression
of
the target
genesLigandbindingenables the TR to releasecorepressors to
recruitactivating partners of transcription (coactivators) and to theninduce
the transcription
of
the target
genes
To
fulfil all
thesefunctions (DNA-binding hormone binding transactivationactivity) the TRs are
organized
into
modules an
N -terminustransactivation domain a DNA-binding domain (DBD) a hingedomain
and a
ligand-binding domain
(LBD) Organized
as
asuccession
of
12
helices this last domain
has on
its C -terminusthe transactivation domain the activity of which is exerted in
the presence
of
the ligand
Indeedmodifications
of
the recep-tor structure occur during hormone binding and involve moreparticularly the 12th helix (H12) which includes the last C -terminus amino acidsIn
the
b
form
of
RTH
the
abnormality
is
carried
by
the
THRB
gene
The
mutations
are
essentially
distributed
over
the
LBD
andthe hinge domain (they do not affect the DNA-binding domainor
the
N -terminus
transactivation
domain)
(1047297 gure
1)
Threeregions rich in cytosine and guanine clusters (CpG islands)are particularly subject to genetic abnormalities (hot spots)[1]
even
though
some
mutations
have
been
reported
outsideof
these
hot
spots
[25] The
two functional
isoforms
producedfrom the THRB gene differing at their N -terminus (TRb1 andTRb2) are both concerned by these
C -terminus abnormalitiesDNA
binding
is
preserved
and
classically
the
mutated
receptorshave a reduced or absence of affinity for T3 They can also havenormal affinity for T3 but a constitutional inability to interactwith
coactivators
[1]
The
phenotype
is
expressed
while
a
singlecopy of the gene is usually involved (heterozygous mutation)The explanation lies in a dominant negative activity exerted bythe mutant receptors on the still functional isoforms By dime-rizing
with
them
they
prevent
the
release
of
the
corepressorsthe recruitment of the coactivators and finally transcriptionalactivity In 90 of cases the identified mutations are missensepoint
mutations
(a
nucleotide
base
is
changed
into
another
resulting
in
an
amino
acid
substitution
on
the
protein
[1])Sometimes
the
point
mutation
is
a
nonsense
mutation
(whichstops protein translation) it may involve the deletion or inser-tion
of
a
nucleotide
base
which
then
leads
to
a
modification
ofthe reading frame and translation of the genetic message intoan erroneous protein message In the case of nonsense muta-tions
or
modifications
of
the
reading
frame
the
affected
recep-tors are truncated on a more or less long part of their
C -terminusCurrently
close
to
500
families
have
thus
been
identified
ascarriers of a THRB gene abnormality and close to 200 different
mutations have been identified (the same mutation may becarried by several different families) [1]As
of
now
there
are
8
known
different
mutations
affecting
theTHRA gene in patients with RTHa (table III ) As with THRB theyare located in the ligand-binding domain (1047297 gure
2) They alsoinvolve
point
mutations
(missense
or
nonsense)
or
abnormali-ties (insertion or deletion of a nucleotide) that result in modifi-cation of the reading frame thus causing a truncated receptorAs with RTHb point mutations seem to be predominant (6 out of8
times)
These
were
de
novo
mutations
in
6
patients
In4 patients the abnormality occurred through autosomal domi-nant transmission by an affected parent (father or mother)Contrary
to
isoforms
TRb1 and
TRb2
which
differ
on
their
N -
terminus
the
main
isoforms
produced
from
the
THRA
geneTRa1
and
TRa2
differ
on
their
C -terminus
They
share
a
commonprotein sequence up until the 360th amino acid the sequencesthen
diverge
resulting
in
a
functional
LBD
for
TRa1
and
an
LBDthat is incapable of binding T3 for TRa2 Six of the eight abnor-malities detected are located in the part of the gene concerningonly
TRa1 [14ndash161920] the
two
others
concern
the
commonsequence between TRa1 and TRa2 [1721] Several of themutations
identified
in
the
THRA
gene
in
cases
of
RTHa
werealso identified in the THRB gene in cases of RTHb A263V (THRA)
Figure
1
The
main
isoforms
produced
by
the
THRB
gene
and
themutations
described
in
the
b
form
of
resistance
to
thyroid
hormonesThe isoforms TRb1 and TRb2 are functional receptors capable of binding DNA and T3
and
influencing under the control of the latter the expression of target genes The
mutations found in RTHb are concentrated in the T3 binding domain (E)and thehinge
domain (D) which separates it from the DNA-binding domain (C) and theN -terminus
transactivation domain (AB) Theyare present in the common sequenceof isoforms
TRb1
and TRb2 Three areas are particularly sensitive to mutations (hot spots) and
are foundbetween aminoacids234and 282 ( 1) 309 and 353 ( 2) and 426 and
460 ( 3 numbering in 461 amino acids of the TRb1
receptor)
TRa
receptor mutations extend the spectrum of syndromes of reduced sensitivity tothyroid hormone ENDOCRINOLOGIE
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and
A317V
(THRB) [17] R384C
and
R438C
[1926] C392X
andC446X
mutations
[2027] Modification
of
the
reading
framefrom amino acid 382 in TRa1 (due to the insertion of a nucleo-tide base in the
THRA gene) [15] has also been reported in the
equivalent
residue
of
TRb1TRb2 (insertions
of
several
bases
inthe THRB gene) [28] although the erroneous consecutivesequence is not the same For the other
THRA gene mutations
with
no
strict
equivalent
in
the
THRB
gene
similar
mutationshave been described either resulting in another substitution oroccurring in a neighbouring residue One notable exceptionhowever is the N359Y mutation [21] which has no strictequivalent
and
in
which
the
corresponding
amino
acid
in
theTRb1TRb2 sequence is not in one of the three known hotspots (a partial explanation for this may lie in the distinctivefeatures
of
the
phenotype
associated
with
this
mutation
see
below)
In
any
case
comparison
of
the a
and b
forms
of
RTH
foridentical
or
equivalent
mutations
enables
the
respective
rolesof the different receptors to be specified In general then the b
receptors
seem
to
be
clearly
involved
in
the
hypothalamic-pituitary feedback loop while the a receptors are more involvedin the peripheral effects of THSeveral
TRa1 mutants
have
been
examined
in
functional
stud-ies Their common points include their incapability to induce theexpression
of
target
genes
and
their
dominant
negative
repres-sor activity over the normal TRa1 receptor [14ndash172129] When
it
was
evaluated
the
affinity
for
T3
was
reduced
[161721]Moreover
the
dominant
negative
activity
seems
to
be
exertedon the TRb1 receptor [152129] The still small number ofreported cases does not enable the formulation of genotypendashphenotype
correlations
For
example
only
two
mutations
affectboth TRa1 and TRa2 While the A263V mutation does not resultin a phenotype different from that observed for mutations thatonly
affect
TRa1 [17]the
phenotype
associated
with
the
N359Ymutation is particular due to the incidence (coincidental) of amarked malformation syndrome and hypercalcemia from para-thyroid hyperplasia and even to the absence of constipation andintellectual
deficit
(though
this
absence
has
also
been
observedin other cases) [21] Whether other isoforms produced from theTHRA
gene (TRa3 p43 P30 TRD1 and TRD2) are implicated inthe
phenotype
also
deserves
to
be
explored
[21] Although
this
needs
to
be
substantiated
with
subsequent
clinical
cases
thereis
a
tendency
for
more
serious
forms
to
exist
with
the
mutationoccurring early in the sequence and resulting in truncation Themost
significant
intellectual
deficit
(IQ
of
22)
was
described
forthe mutation involving the 18 amino acid deletion of TRa1 [20]Conversely patients with normal IQs are carriers of missensepoint
mutations
that
only
substitute
one
amino
acid
for
another[2021] In RTHb the severe forms are also often related toTRb1TRb2
truncations
[28] It
is
likely
that
truncations
(result-ing in the lack of C -terminal helix 12) induce more severe
TABLE IIIDescription
of
the
known
mutations
in
THRA
gene
(encoding
the
thyroid
hormone
receptor
TRa1)
in
patients
with
the a
syndrome
of
resistance
to
thyroid
hormone
Protein
mutation1
Number of
involvedfamilies
Number of
involvedpatients
THRA gene mutations2 Type of protein
mutation
Consequences for protein
functions
Involved
isoforms
References
A263V 1 3 Single base substitution (CxxxxT) Missense Single aminoacid substitution TRa1TRa2
[17]
N359Y 1 1 Single base substitution (C1075G) Missense Single aminoacid substitution TRa1TRa2
[21]
A382fs388X 1 1 Single base deletion(1144delG)
Frameshift Wrong sequence from A382then premature truncation at
position 388
TRa1 [16]
R384C 1 1 Single base substitution (C1150 T) Missense Single aminoacid substitution TRa1 [19]
C392X 1 1 Single base substitution (C1176A) No-sense Premature truncation atposition C392
TRa1 [20]
F397fs406X 1 2 Single base insertion(1144insT) Frameshift
Wrong sequence from F397then premature truncation atposition 406
TRa1 [1518]
P398R 1 1 Single base substitution (C1150 T) Missense Single aminoacid substitution TRa1 [20]
E403X 3 4 Single base substitution (C1176A) No-sense Premature truncation atposition E403
TRa1 [1420]
1The numbering is based on the TRa1 protein sequence (common to the TRa2 sequence until the amicoacid 360)2All mutations are located in exon 9 of the THRA gene (last exon of TRa1 and the secondlast for TRa2)
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Figure 2
The
main
isoforms
produced
by
the
THRA
gene
and
the
mutations
described
in
the
a
form
of
resistance
to
thyroid
hormonesIsoform TRa1 isa functional receptor capable of binding DNA and T3 and influencingunder thecontrolof thelatter theexpression of target genes Isoform TRa2
is incapable of
binding thehormoneand behaves like a weak dominant negative inhibitor of the T3 functionalreceptorsFor now themutations found in RTHa rein the T3 binding domain (E)
while
thehinge domain(D) theDNA-binding domain (C)and theN -terminus transactivation domain (AB) arespared Themutationsconcern the commonsequence of thetwo
isoforms TRa1andTRa2 oronlyaffectthe C -terminussequence of TRa1 (numbering in410 amino acids ofthe TRa1 receptor) Thepoint mutations arerepresentedby a star and
the
frameshift mutations by a star at the level of the first mutated amino acid fol lowed by a blue box representing the modified sequence
The four mutations introduced in the THRA gene to try to generate murine models of the a form of resistance to thyroid hormones are also indicated in italic font (R384C
P394fs406X P398H and L400R) The numbering for the murine isoform TRa1
is the same as for the human isoform
TRa receptor mutations extend the spectrum of syndromes of reduced sensitivity tothyroid hormone ENDOCRINOLOGIE
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phenotype by profoundly affecting TR function through totalinability
to
interact
with
coactivatorsThe genotypendashphenotype correlations may in fact need to beinvestigatedin
animal
modelsMicewith
complete
inactivationof the THRA andor
THRB genes have been reported [11] but
may not represent the most relevant models as the absence ofa receptor does nothave the same consequences as the expres-sion
of
an
abnormal receptor
The comparison
is
more
logical inanimal
models
with
an
artificially
introduced
mutation For theTHRA
gene thereare fourdifferentmodels available that are allbased
on
a
mutation
of
the hormone-binding domain in
onlythe TRa1 receptor (1047297 gure 2 no model with mutation affectingTRa1
and TRa2)
One model
introduced
in
TRa1 the PV
muta-tion [13] which was identified in a patientwith RTHb (insertionof
several
nucleotides
with
modification of
the reading
frame)[30]
while
the others
introduce
point
mutations
R384C
[29](corresponding exactly to a
THRA mutation in a patient with
RTHa
[19])
L400R
[31]
and P398H
[32] These models
providephenotypic data that are complementary to those reported inhuman cases The growth retardation with impairment in ossi-fication is consistent in all animals [132931ndash34] The role ofTRa1
in
the development
of
chondrocytes
is probably a
deter-mining factor
as
the
elective introduction
of
the
L400R
muta-tion in the chondrocytes is sufficient to induce the phenotype[35]
The severity
of
the bone phenotype however
is
variabledepending on the models The bone phenotype of the R384Cmutation for instance was observed in young mice and dis-appeared in
the adultmice
[29]
In humans this
mutationwasreported in
a
girl though
it
is
only
known that
she
was
a
carrierof a familial form of autism without other information on herphenotype It is interesting to observe that the R384C mice hadsignificant psychomotor
disorders
with
anxiety memoryimpairment and depression (which are possible even fre-quent manifestations of autism) [3637] Cerebellar ataxiawas
also
observed
in
another
model
[31]
which
is
somewhatsimilar to the clumsiness and awkwardness described in thegait or the handling of objects in several patients with RTHa[141617] In animals these psychoneuromotor disorders arerelated
to impairment
of
neurogenesis
in
the hippocampus(lack of certain GABAergic interneurons) [38] and diminishpartially with levothyroxine [3638] This reduction on treat-ment
is not
observed
for the
bone
phenotype [39] as
was
also
reported in
humans Another
common
point of
the animalmodels
with
TRa1 mutations
is the
near-normality
of
TH
serumlevels On the other hand TSH has been found to be high inseveral
models
[1332]
as
opposed to its usual observed nor-mality in patients with RTHa (high-normal values in one case[16]) The T4T3 ratio and the reverse T3 (rT3) found to be lowin
patients with
RTHa
are
considered
an
indication of
theperipheral metabolism of TH Interestingly high levels of type1
deiodinase
(responsible for the conversion
of
T4
into
T3 andfor the clearance of rT3)have been measured in the liver of one
of the murine models [13] Normal levels were however
detected
in
another [31]Investigations of murine models found bradycardia [293132]which
was
rather
mild
but
accompanied
by
inadaptation
tostress [40] Bradycardia was reported in patients with RTHa
[141617] but the rare functional heart explorations that weredone did not demonstrate serious abnormalities [16] Bradycar-dia
is
probably
the
result
of
the
direct
effect
of
TH
on
themyocardium
(known
target
tissue
of
TH
expressing
ratherTRa1) abnormalities of calcium flux and contractility wereobserved
in
one
model
[41] However
there
is
probably
anothermechanism involved namely deregulation of the autonomicnervous
system
due
to
abnormal
brain
development
[4042]The same mechanism (lack of cerebral control on the autonomicnervous
system)
has
been
suggested
as
an
explanation
forthermogenesis
abnormalities
These
abnormalities
have
notbeen actually reported (not explored) in patients with RTHa
A
reduction
in
body
temperature
andor
a
cold
intolerance
wasdescribed in two murine models [3132] Dysfunction of thebrown fat is suspected related to deregulation of the autonomicnervous system caused by abnormal brain development [38]Increased
vasodilatation
again
related
to
the
autonomic
ner-vous
system
was
supposedly
also
observed
in
one
of
the
mo-dels with abnormal thermogenesis [43]One
patient
with
RTHa
had
weight
loss
(occurring
in
childhoodand continuing in adulthood) [21] while the other patients hadnormal or increased weight [15ndash18] One murine model exhib-ited
overweight
(without
increased
food
intake)
hepatic
stea-tosis
and
insulin
resistance
[32] but
a
controversy
exists
aboutthe real responsibility of THRA mutation Two others models hadhyperphagia without weight gain resistance to tube-feedingmild
adiposity
due
to
impairment
of
adipogenesis
and
low
liverconcentrations of lipids [44ndash46] The same mechanism aninteraction with PPARg has been suggested in both of thesecontrary
situations
[4547]
ConclusionsTowards the end of the 1980s the first descriptions of abnor-malities of the
THRB gene in patients with RTHb generated a
very
large
number
of
questions
about
the
possibility
of
muta-tions
in
the
THRA
gene
Answers
have
arrived
more
than
20
yearslater with the description of clinical phenotypes that are quite
particular
abnormalities
suggestive
of
mild
untreated
congeni-tal hypothyroidism in conjunction with thyroid function teststhat are more or less normal and therefore discordant For themoment
suggestive
symptoms
are
short
stature
hypothyroid-ism-like
facial
shape
and
low
T4T3
ratio
It
is
worthy
to
notethat
the
whole
exome
database
(httpexacbroadinstituteorg) contains 68
THRA missense or frameshift mutations with
most
of
them
predicted
to
alter
TRa1 function
It
is
thereforelikely that several patients in the general population haveundiagnosed RTHa with milder phenotype As in RTHb it is
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the discordance between the clinical and the laboratory datathat
should
stand
out
for
the
clinician
The
identification
ofpatients with authenticated abnormalities of the
THRA gene
is
essential
for
improving
the
definition
of
the
clinical
spectrumof RTHa and more generally of all RTH and syndromes of
reduced sensitivity to thyroid hormones This improved pheno-typic definition will enable genotypendashphenotype correlations tobe
formulated
and
perhaps
the
development
of
therapeuticguidelines
The
reported
cases
show
that
the
administrationof TH in patients with RTHa does not improve all the symptomsprobably
because
the
therapeutic
management
occurs
too
latefor certain abnormalities that have already become definitivelyestablished
andor
because
the
tissue
resistance
is
too
severeThe extreme dependence for TH during the brain development isa
clear
example
of
the
need
for
early
treatment
The
significance
of this seems to depend partially on the nature of the underlyinggenetic
abnormality
The
different
murine
models
with
diversegenetic abnormalities may thus be valuable tools for testing thetherapeutic
approaches
Assuming
that
the
resistance
is
toosevere to be managed by hormonal treatment identification
of the major role in animals of the interaction of mutated TRa1with corepressors such as NCoR [48] was crucial Indeed it ledto
the
demonstration
of
the
partial
reversal
of
the
abnormalTHRA
gene
phenotype
through
the
coexpression
of
a
mutantNCoR unable to interact with the TRs [49] and through theadministration
of
an
inhibitor
of
the
corepressors-associatedhistone deacetylase activity [50]
Disclosure of interest the authors declare that they have no conflicts ofinterest concerning this article
References[1] Dumitrescu AM Refetoff S The syndromes
of reduced sensitivity to thyroid hormoneBiochim Biophys Acta 201318303987ndash 4003
[2] Refetoff S DeWind LT
DeGroot LJ Familialsyndrome combining deaf-mutism stuppledepiphyses goiter and abnormally high PBIpossible target organ refractoriness to thyroidhormone J Clin Endocrinol Metab196727279ndash 94
[3] Sakurai A TakedaK Ain K Ceccarelli P NakaiA Seino S et al Generalized resistance tothyroid hormone associated with a mutationin the ligand-binding domain of the humanthyroid hormone receptor beta Proc Nat l
Acad Sci U S A 1989868977ndash 81
[4] Vlaeminck-Guillem V Margotat A Torresani J DHerbomez M Decoulx M Wemeau JLResistance to thyroid hormone in a familywith no TRbeta gene anomaly pathogenichypotheses Ann Endocrinol (Paris)200061149ndash 94
[5] Weiss RE
Hayashi Y
Nagaya T
Petty KJMurata Y Tunca H et al Dominant inheri-tance of resistance to thyroid hormone notlinked to defects in the thyroid hormonereceptor alpha or beta genes may be dueto a defective cofactor J Clin EndocrinolMetab1996814196ndash 203
[6] Pohlenz J Weiss RE
Macchia PE Pannain SLau IT Ho H et al Five new families with
resistance to thyroid hormone not caused bymutations in the thyroid hormone receptorbeta gene J Clin Endocrinol Metab1999843919ndash 28
[7] DumitrescuAM Liao XH Abdullah MS Lado-Abeal J Majed FA Moeller LC et al Muta-tions in SECISBP2 result in abnormal thyroidhormone metabolism Nat Genet2005371247ndash 52
[8] Dumitrescu AM Liao XH Best TB Brock-mann K Refetoff S A novel syndromecombining thyroid and neurological
abnormalities is associated with mutationsin a monocarboxylate transporter gene Am J Hum Genet 200474168ndash 75
[9] Friesema EC Grueters A
Biebermann HKrude H von Moers A Reeser M et alAssociation between mutations in a thyroidhormone transporter and
severe X-linked psy-chomotor retardation Lancet 20043641435ndash 7
[10] Refetoff S Bassett JH
Beck-Peccoz P Bernal JBrent G Chatterjee K et al Classificationandproposednomenclaturefor inheriteddefects ofthyroid hormone action cell transport andmetabolism Eur Thyroid J 201437ndash 9
[11] Vlaeminck-Guillem V Wemeau JL
Physiolo-gie et physiopathologie des reacutecepteurs thyr-oiumldiens lapport des modegraveles murins AnnEndocrinol (Paris) 200061440ndash 51
[12] Wikstrom L Johansson C Salto C Barlow CCampos Barros A Baas F et al Abnormalheart rate and body temperature in micelacking thyroid hormone receptor alpha 1EMBO J 199817455ndash 61
[13] Kaneshige M Suzuki H Kaneshige K Cheng J Wimbrow H Barlow C et al A targeteddominant negative mutation of the thyroidhormone alpha 1 receptor causes increasedmortality infertility and dwarfism in miceProc Natl Acad Sci U S A 20019815095ndash 100
[14] Bochukova E Schoenmakers N Agostini M
Schoenmakers E RajanayagamO Keogh JMet al A mutation in the thyroid hormonereceptor alpha gene N Engl J Med2012366243ndash 9
[15] van Mullem A van Heerebeek R Chrysis DVisser E Medici M Andrikoula M et alClinical phenotype and mutant TRalpha1 NEngl J Med 20123661451ndash 3
[16] Moran C
Schoenmakers N Agostini MSchoenmakers E Offiah A
Kydd
A et alAn adult female with resistance to thyroidhormone mediated by defective thyroid
hormone receptor alpha J Cl in EndocrinolMetab 2013984254ndash 61
[17] Moran C Agostini M Visser WE Schoen-makers E SchoenmakersN Offiah AC etalResistance to thyroid hormone caused by amutation in thyroid hormone receptor (TR)alpha1 and
TRalpha2 clinical biochemicaland genetic analyses
of three
related patientsLancet Diabet Endocrinol 20142619ndash 26
[18] van Mullem AA Chrysis D Eythimiadou AChroni E Tsatsoulis A de Rijke YB et alClinical phenotype of a new type of thyroidhormone resistance caused by a mutation ofthe TRalpha1 receptor consequences of LT4
treatment J Clin Endocrinol Metab2013983029ndash 38
[19] Yuen RK Thiruvahindrapuram B Merico DWalker S Tammimies K Hoang N et alWhole-genome sequencing of quartetfamilies with autism spectrum disorder NatMed 201521185ndash 91
[20] Tylki-Szymanska A Acuna-Hidalgo R Kra- jewska-Walasek M Lecka-Ambroziak ASteehouwer M Gi lissen C et al Thyroidhormone resistance syndrome due to muta-tions in the thyroid hormone receptor alphagene (THRA) J Med Genet 201552312ndash 6
[21] Espiard S Savagner F
Flamant F
Vlaeminck-Guillem V Guyot R Munier M
et al A novelmutation in THRA gene associated with an
atypical phenotype of resistance to thyroidhormone J Clin Endocrinol Metab 2015 jc20151120
[22] Faivre L Cormier-Daire V GenevieveD PintoG Goulet O
Munnich A
et al A novelsyndrome with dwarfism poorly muscledbuild absent clavicles humeroradial fusionslender bones oligodactyly and micro-gnathia Clin Dysmorphol 200110181ndash 4
[23] Mundlos S Cleidocranial dysplasia clinicaland molecular genetics J Med Genet199936177ndash 82
TRa receptor mutations extend the spectrum of syndromes of reduced sensitivity tothyroid hormone ENDOCRINOLOGIE
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[24] Mundlos S Otto F
Mundlos C Mulliken JBAylsworth AS Albright S et a l Mutat ionsinvolving the transcription factor CBFA1
causecleidocranial dysplasia Cell 199789773ndash 9
[25] Margotat A
Sarkissian G Malezet-Desmou-lins C Peyrol N Vlaeminck Guillem V
Wemeau JL
et al Ident if ication of eightnew mutations in the c-erbAB gene ofpatients with resistance to thyroid hormoneAnn Endocrinol 200162220ndash 5
[26] Adams M Matthews C Coll ingwood TNToneY
Beck-Peccoz P ChatterjeeKK Geneticanalysis of 29 kindreds with generalized andpituitary resistance to thyroid hormone Iden-tification of thirteen novel mutations in thethyroid hormone receptor beta gene J ClinInvest 199494506ndash 15
[27] Groenhout EG Dorin RI Generalized thyroidhormone resistance due to a deletion of thecarboxy terminus of the c-erbA beta receptorMol Cell Endocrinol 19949981ndash 8
[28] Wu SY CohenRN SimsekE Senses DA Yar
NE Grasberger H et al A novel thyroidhormone receptor-beta mutation that failsto bind nuclear receptor corepressor in apatient as an apparent cause of severe pre-dominantly pituitary resistance to thyroid hor-mone J Clin Endocrinol Metab 2006911887ndash 95
[29] Tinnikov A Nordstrom K Thoren P Kindblom JM Malin S Rozell B et al Retardation ofpost-natal development caused by a nega-tively acting thyroid hormone receptoralpha1 EMBO J 2002215079ndash 87
[30] Parrilla R
Mixson AJ McPherson JA
McClas-key JH Weintraub BD Characterization ofseven novel mutations of the c-erbA betagene in unrelated kindreds with generalizedthyroidhormone resistance Evidence for twohot spot regions of the l igand bindingdomain J Clin Invest 1991882123ndash 30
[31] Quignodon L VincentS Winter H Samarut JFlamant F A point mutation in the
activationfunction2 domainof thyroidhormonereceptoralpha1 expressed after CRE-mediated recom-bination partially recapitulates hypothyroid-ism Mol Endocrinol 2007212350ndash 60
[32] Liu YY
Schultz JJ
Brent GA A thyroidhormone receptor alpha gene mutation
(P398H) is associated with visceral adiposityand impaired catecholamine-stimulated lipo-lysis in mice J Biol Chem 200327838913ndash 20
[33] OShea PJ Bassett JH ChengSY Williams GRCharacterization of skeletal phenotypes ofTRalpha1 and TRbeta mutant mice implica-
tions for tissue thyroid status and T3 targetgene expression Nucl Recept Signal 20064e011
[34] OShea PJ Bassett JH Sriskantharajah S YingH Cheng SY Williams GR Contrasting ske-leta l phenotypes in mice with an identicalmutation targeted to thyroid hormone recep-tor alpha1 or beta Mol Endocrinol2005193045ndash 59
[35] Desjardin C
Charles C
Benoist-Lasselin CRiviere J Gilles M Chassande O et alChondrocytes play a major role in the stimu-lation of bone growth by thyroid hormoneEndocrinology 20141553123ndash 35
[36] Venero C Guadano-Ferraz A Herrero AINordstrom K Manzano J de Escobar GM
et al Anxiety memory impairmentand loco-motor dysfunction caused by a mutant thyr-oid hormone receptor alpha1 can beameliorated by T3 treatment Genes Dev2005192152ndash 63
[37] Pilhatsch M
Winter C
Nordstrom K Venn-strom B Bauer M
Juckel G Increaseddepressive behaviour in mice harboring themutant thyroid hormone receptor alpha 1Behav Brain Res 2010214187ndash 92
[38] Kapoor R
van Hogerlinden M
Wallis KGhosh H Nordstrom K Vennstrom Bet al Unliganded thyroid hormone receptoralpha1 impairs adult hippocampal neurogen-esis FASEB J 2010244793ndash 805
[39] Bassett JH Boyde A Zikmund T Evans HCroucher PI
Zhu X
et al
Thyroid hormonereceptor alpha mutation causes a severe
andthyroxine-resistant skeletaldysplasiain femalemice Endocrinology 20141553699ndash 712
[40] Mittag J Davis B Vujovic M Arner AVennstromB Adaptations of theautonomousnervous system controlling heart rate areimpairedby amutant thyroid hormone recep-tor-alpha1 Endocrinology 20101512388ndash 95
[41] Tavi P Sjogren M Lunde PK Zhang SJAbbate F
Vennstrom B et al Impaired
Ca2+ handling and contraction in cardiomyo-cytes from mice with a dominant negativethyroid hormone receptor alpha1 J Mol CellCardiol 200538655ndash 63
[42] Mittag J Lyons DJ Sall strom J Vujovic MDudazy-Gralla S Warner A
et al Thyroid
hormone is required for hypothalamic neu-rons regulating cardiovascular functions J ClinInvest 2013123509ndash 16
[43] Warner A RahmanA Solsjo P Gottschling KDavis B Vennstrom B et al Inappropriateheatdissipation ignitesbrown fat thermogen-esis in mice with a mutant thyroid hormonereceptor alpha1 Proc Natl Acad Sci U S A201311016241ndash 46
[44] SjogrenM AlkemadeA
MittagJ
NordstromK KatzA Rozell B etal Hypermetabolisminmice caused by the central action of an unli-ganded thyroid hormone receptor alpha1EMBO J 2007264535ndash 45
[45] Ying H Araki O Furuya F Kato Y Cheng SYImpaired adipogenesis caused by a mutated
thyroid hormone alpha1 receptor Mol CellBiol 2007272359ndash 71
[46] Araki O
Ying H Zhu XG Willingham MCChengSY Distinct dysregulationof lipid meta-bolismbyunligandedthyroid hormone recep-tor isoforms Mol Endocrinol 200923308ndash 15
[47] Liu YY
Heymann RS Moatamed F
Schultz JJSobel D Brent GA A mutant thyroid hor-mone receptor alphaantagonizesperoxisomeproliferator-activated receptor alpha signalingin vivo and impairs fatty acid oxidation Endo-crinology 20071481206ndash 17
[48] Fozzatt i L Lu C
Kim DW Cheng SY Differ-ential recruitment of nuclear coregulatorsdirects the isoform-dependent action ofmutant thyroid hormonereceptorsMol Endo-crinol 201125908
ndash 21
[49] Fozzatti
L Kim
DW
ParkJW Willingham
MCHollenberg AN Cheng SY Nuclear receptorcorepresso r (NCOR1) regulates in vivoactions ofa mutated
thyroid
hormone recep-tor alpha Proc Natl
Acad
Sci U S A20131107850ndash 5
[50] Kim DW ParkJW
Willingham MC Cheng SYA histone deacetylase inhibitor improveshypothyroidism caused by a TRalpha1mutant Hum Mol Genet 2014232651ndash 64
V Vlaeminck-Guillem S Espiard F Flamant J-LWeacutemeau
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IntroductionThe syndromes of reduced sensitivity to thyroid hormone (TH)[1]
were
long
limited
only
to
resistance
to
thyroid
hormone(RTH) due to an abnormality of the beta form of the thyroidhormone receptor (TRb) with the first clinical description occur-
ring
in
1967
[2]
and
the
first
demonstration
of
the
underlyingmolecular mechanism in 1989 [3] The secondary description oftypical
sporadic
and
familial
cases
though
without
identifiedabnormality of the
THRB (thyroid hormone receptor beta) gene
(currently
estimated
at
about
15
of
cases)
quickly
suggestedthe possibility of other molecular causes for the lack of tissuesensitivity to the action of TH [4ndash6] It was not until the mid-2000s
that
abnormalities
in
transmembrane
transport
and
THmetabolism were described as the cause of this reduced sensi-tivity
of
target
tissues
to
TH
action
affecting
respectively
theMCT8 gene (monocarboxylate transporter 8) and the SBP2 gene(selenocysteine
insertion
sequence-binding
protein
2)
[7ndash10]The responsibility of the
THRA (thyroid hormone receptor alpha)
gene which encodes the other functional TH receptor (TRa1)had
been
suggested
but
could
not
be
demonstrated
Whileviable murine models (review in [11]) of inactivation [12] ormutation
[13]
in
the
THRA
gene
have
rapidly
been
publishedmutations in humans were considered by the simple reason oftheir absence to be extremely rare lethal or subclinicallyexpressed The phenotype of patients in whom
THRA gene
mutations
were
finally
described
is
retrospectively
suggestiveof
that
described
over
10
years
previously
in
murine
models
It
isremarkable however to notice that the first case of RTH due toTRa
abnormality
(named
RTHa in
contrast
with
RTHb
[10])recognized as a state of hypothyroidism with normal thyroid
function
test
was
not
identified
in
2012
through
direct
targetingbut
during
whole
genome
sequencing
[14]
Likewise
the
twoother
cases
described
in
the
same
year
were
discovered
througha
candidate
gene
approach
after
ruling
out
an
abnormalityaffecting a TH transporter or deiodinase [15] Patients indeedpresent
with
quite
normal
thyroid
laboratory
testing
a
confus-ing situation that usually lead patients to present themselves innon-endocrinological clinical departmentsThe
molecular
decoding
of
RTHa has
only
just
begun
and
thedescription of at least several tens of cases will be able to
precisely delineate its clinical spectrum At present only14
patients
with
RTHa
have
been
found
in
the
literatureamongst 9 distinct families [14ndash21] And although their commonclinical aspects are emerging the analysis also clearly showsdiversity
in
the
phenotype
The
purpose
of
this
review
is
topresent published cases of RTHa and to provide details on theirunderlying
molecular mechanisms particularly in the light ofavailable
murine
models
The
objective
is
to
thus
promote
thediagnostic
identification
of
patients
in
order
to
better
define
theextent of the clinical manifestations related to congenital anom-alies of TH action
Clinical presentation and biologyAlthough
14
patients
with
identified
genetic
abnormalities
havebeen reported in the literature clinical data for only 13 of themare
available
The
genetic
identification
for
the
fourteenth
wasdone as part of whole genome sequencing in subjects withfamilial forms of autism [19] Abnormality of the
THRA gene was
not specifically investigated and no description of the case wasavailable
other
than
the
fact
that
the
female
patient
who
wasautistic had a brother who was also an autistic non-carrier of theTHRA
mutation [19]The patients included 9 women and 5 menbut
it
is
too
early
to
define
a
sex
ratio
(it
is
11
in
RTHb [1])
Thecases were sporadic (de novo mutation) or familial (mutationtransmitted by a parent who was a carrier) In the reportedcases
the
age
at
the
molecular
diagnosis
varied
(seven
childrenor adolescents and seven adults) which contributes to certainvariations in the clinical descriptions and even in the adultsuncertainty as to the description of the phenotype in childhoodThe
clinical
presentation
of
RTHa
always
includes
although
to
varying
degrees
the
combination
of
a
dysmorphic
syndromeand psychomotor development disorders (table
I ) Of note is theabsence
of
goiter
which
is
usually
among
the
typical
manifes-tations of RTHb Generally there are signs of mild to moderateuntreated
congenital
hypothyroidism
The
near-normal
valuesof the laboratory thyroid function tests (cf below) must thensignal
the
possibility
of
RTHa
and
prompt
a
genetic
analysis
ofthe patient The manifestations related to hypothyroidism thusreported are mild to moderate intellectual deficit decreasedstature
alterations
in
ossification
macroglossia
and
chronic
une
hypothyroiumldie
congeacutenitale
modeacutereacutee
non
traiteacutee
et
une
(quasi-)
normaliteacute
des
formes
libres
et
totales
des
hormones
thyroiumldiennes
et
de
la
TSH
(le
ratio
T4T3
est
toutefois
habituellement
diminueacute) Le pheacutenotype peut inclure agrave des degreacutes divers une courte taille (par retard de
croissance)
un
syndrome
dysmorphique
(face
et
extreacutemiteacutes
des
membres)
des
troubles
neuro-psychomoteurs
une
constipation
et
une
bradycardie
Les
anomalies
geacuteneacutetiques
ont
eacuteteacute
identi 1047297 eacutees dans le domaine de liaison du ligand et aboutissent agrave un deacutefaut de liaison de la T3 uneinteraction
anormalement
forte
avec
les
coreacutepresseurs
et
une
activiteacute
dominante
neacutegative
sur
les
reacutecepteurs
resteacutes
fonctionnels
La
reconnaissance
des
cas
et
lidenti 1047297 cation
des
mutations
sous-
jacentes
sont
indispensables
pour
mieux
deacute1047297 nir le
spectre
des
syndromes
de
sensibiliteacute
reacuteduite
aux hormones thyroiumldiennes
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constipation
The
dysmorphic
syndrome
combines
small
staturedecreased
limb
length
with
a
trunk
that
is
of
rather
normal
size(even elongated in the thoracic portion) and multiple facialanomalies
that
may
include
macrocephaly
(the
need
for
acaesarean section was reported several times) rather coarsefeatures hypertelorism of the eyeballs a short and wide nosemicrognathism
delayed
tooth
eruption
a
short
neck
or
evenmacroglossia The decreased stature is related to growth retar-dation
(sometimes
detected
in
utero)
and
can
even
border
ondwarfism [21] The feet and hands may be enlarged
Malformations
have
also
been
reported
such
as
congenitalhip
dislocation
or
coxa
valga
One
described
case
included
aunique malformation syndrome (sufficiently significant to pro-voke
a
separate
publication
more
than
10
years
before
thediscovery of the molecular substratum [22]) with bilateralagenesis of the clavicles unilateral humero-radial synostosiselbow
dislocation
syndactyly
of
the
4th
and
5th
toes
absence
ofthe 12th rib scoliosis and hip dysplasia [21] (presentationsuggestive
of
cleidocranial
dysostosis
[2324]) With
regard
topsychomotor status there have been reports of abnormalities in
TABLE IClinical
phenotype
of
the
14
published
cases
of
resistance
to
thyroid
hormone
due
to
a
defective
TRa
receptor
Gender Females n = 9Males n = 5
Age at the molecular diagnosis Childrenteenagers 6 to 18 years (n = 7)Adults 25 to 60 years (n = 7)
Origin European Caucasian n = 13North-American n = 1
Dysmorphic syndrome
Figure
Growth retardation n = 10Height Small in 9 patients Normal in 3 patients
Weight Thinness n = 1Ideal weight n = 3
Overweight n = 1Obesity n = 3
Long thorax n = 6Short limbs n = 7 No in 3 other patients
Face dysmorphism
Macrocephaly n = 11Coarse facial features n = 6 (no in a
7th patient)
Eye hypertelorism n = 7Flat nasal bridge upturned nose n = 8Short neck n = 4 (no in a 5th patient)
Micrognathia n = 2Macroglossia n = 5 (no in a 6th patient)
Delayed tooth eruption n = 2Malformations n = 5Ends of the limbs n = 3 (congenital dislocation coxa valga)Hip n = 1Cleidocranial dysplasia n = 5
Cognition disorders
Psychomotor disorders Yes n = 7
No n = 7Cognitive defect No defect n = 2
Mild defect n = 7Moderate to severe defect n = 4
Bradycardia n = 5 (no in 3 other patients)
Constipation n = 11 (no in a 12th patient)
Hypercholesterolemia n = 11 (no in a 12th patient)
Anemia Microcytic n = 10Macrocytic n = 3
TRa receptor mutations extend the spectrum of syndromes of reduced sensitivity tothyroid hormone ENDOCRINOLOGIE
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coordination learning to walk and reading Mild to severeintellectual
deficit
has
often
been
reported
but
is
not
systematic[2021] Constipation is nearly constant with an early appear-ance
in
childhood
one
case
of
diarrhoea
occurring
late
inadulthood was described [21] Bradycardia another sign sug-
gestive of hypothyroidism is sometimes reported [141617]Overweight is also possible particularly in adults [15ndash18] Bodytemperature
appears
normal
[1518] whereas
the
baselinemetabolism
is
decreased
[14161721] Finally
cases
of
carpaltunnel syndrome have been reported [17] as is sometimesdescribed
in
association
with
myxoedema
of
hypothyroidismThe routine laboratory tests are normal except for anaemiawhich
is
consistently
present
in
all
clinical
descriptions
but
israther moderate It is usually normocytic though sometimesmacrocytic
[1721]) Hypercholesterolemia
may
also
occur[15ndash1820] Insulin-like
growth
factor
1
may
be
low
in
childrenand adolescents patients [14ndash1618]
Radiological
exams
are
done
to
investigate
potential
malforma-tion syndromes [2021] Skull X-rays in children confirm macro-cephaly and show delay of ossification in the fontanels and thepersistence of wormian bones (which reflect ossification abnor-malities)
[14]
Ossification
delay
is
also
evidenced
by
epiphysealdysgenesis
(femoral
heads)
[141518]
and
by
delayed
boneage An ovoid appearance of the vertebrae is possible [20] Inadults
X-rays
again
show
macrocephaly
with
thickening
of
theskull vault (occipital in particular) and enlargement of the frontalbone [1617] Cortical bone thickening has also been describedon
the
long
bones
of
the
limbs
[16] Osteodensitometric
meas-urements
in
adults
are
usually
normal
[16ndash1821]The signs of hypothyroidism that are typically found lead logi-cally to an investigation of thyroid function tests Though pro-viding
reassurance
when
values
are
normal
or
low
normal
they
must attract attention when there is a discrepancy with the
clinical
presentation
It
is
this
dissociation
between
normallaboratory values and the more or less pronounced signs ofhypothyroidism
(including
the
dysmorphic
syndrome)
thatshould suggest the diagnosis of RTHa It is the opposite condi-
tion of RTHb where the symptoms of hyperthyroidism are ratherminimal in association with laboratory indications of hyperthy-roidism
(table
II )
In
this
respect
it
can
be
seen
that
thedissociation
between
the
clinical
and
laboratory
observationsis a key element of RTH both in the alpha and the beta formsThe
thyroid
hormone
values
both
in
their
free
and
total
formsare more or less normal There is a tendency however for T4 tobe
slightly
low
and
T3
slightly
high
As
a
result
there
is
adecreased T4T3 ratio which was the only consistent factorin
all
the
published
cases
The
TSH
is
normal
(though
low
insome
cases)
It
should
be
noted
that
neonatal
screening
forhypothyroidism which is based on TSH cannot identify RTHa
Several
patients
received
treatment
with
levothyroxine
some-times even before the clinical or specific molecular diagnosisThe clinical effects are inconclusive particularly because cogni-tive disorders and dysmorphic syndrome are often alreadyestablished
and
definitive
[14] Benefits
can
be
seen
for
brady-cardia
energy
levels
bowel
function
and
carpal
tunnel
syn-drome [1617] There is usually an increase in the concentrationsof
thyroid
hormones
and
a
quick
and
predictable
suppression
ofTSH which reflects the successful adaptation of the hypotha-lamic-pituitary axis Improvement of the other abnormal labo-ratory
values
(blood
cholesterol
anaemia)
is
not
constant
Molecular bases of RTHa
The functional thyroid receptors are the isoforms TRb1 TRb2andTRa1 They are present in the nucleus of the target cells as
TABLE IIClinical
and
biological
phenotypes
of
the
a
and
b
syndromes
of
resistance
to
thyroid
hormones
RTHa RTHb
Involved gene THRA THRB
Involved receptors TRa11 TRb1TRb2
Clinical phenotype Mild hypothyroidism(short height dysmorphic syndrom)
Mild hyperthyroidism (tachycardia nervousness)
Goiter No Yes
fT3 High-normal High
fT4 Low normal High
T4T3 ratio Low Low
TSH Normal or low High
1Some mutations of the THRA gene also involve non-functional isoforms such as the TRa2 protein
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dimers They are capable of binding on theDNA specific targetsequences (thyroid
hormone response elements
or
TREs)which are located in the regulatory sequences (promotersenhancers) of
the target
genes Like the other
nuclear
recep-tors they in fact behave like ligand-inducible transcription
factors In the absence of hormones and through interactionwith cofactors that repress their transcriptional activity (core-pressors) the
TR reduces
the expression
of
the target
genesLigandbindingenables the TR to releasecorepressors to
recruitactivating partners of transcription (coactivators) and to theninduce
the transcription
of
the target
genes
To
fulfil all
thesefunctions (DNA-binding hormone binding transactivationactivity) the TRs are
organized
into
modules an
N -terminustransactivation domain a DNA-binding domain (DBD) a hingedomain
and a
ligand-binding domain
(LBD) Organized
as
asuccession
of
12
helices this last domain
has on
its C -terminusthe transactivation domain the activity of which is exerted in
the presence
of
the ligand
Indeedmodifications
of
the recep-tor structure occur during hormone binding and involve moreparticularly the 12th helix (H12) which includes the last C -terminus amino acidsIn
the
b
form
of
RTH
the
abnormality
is
carried
by
the
THRB
gene
The
mutations
are
essentially
distributed
over
the
LBD
andthe hinge domain (they do not affect the DNA-binding domainor
the
N -terminus
transactivation
domain)
(1047297 gure
1)
Threeregions rich in cytosine and guanine clusters (CpG islands)are particularly subject to genetic abnormalities (hot spots)[1]
even
though
some
mutations
have
been
reported
outsideof
these
hot
spots
[25] The
two functional
isoforms
producedfrom the THRB gene differing at their N -terminus (TRb1 andTRb2) are both concerned by these
C -terminus abnormalitiesDNA
binding
is
preserved
and
classically
the
mutated
receptorshave a reduced or absence of affinity for T3 They can also havenormal affinity for T3 but a constitutional inability to interactwith
coactivators
[1]
The
phenotype
is
expressed
while
a
singlecopy of the gene is usually involved (heterozygous mutation)The explanation lies in a dominant negative activity exerted bythe mutant receptors on the still functional isoforms By dime-rizing
with
them
they
prevent
the
release
of
the
corepressorsthe recruitment of the coactivators and finally transcriptionalactivity In 90 of cases the identified mutations are missensepoint
mutations
(a
nucleotide
base
is
changed
into
another
resulting
in
an
amino
acid
substitution
on
the
protein
[1])Sometimes
the
point
mutation
is
a
nonsense
mutation
(whichstops protein translation) it may involve the deletion or inser-tion
of
a
nucleotide
base
which
then
leads
to
a
modification
ofthe reading frame and translation of the genetic message intoan erroneous protein message In the case of nonsense muta-tions
or
modifications
of
the
reading
frame
the
affected
recep-tors are truncated on a more or less long part of their
C -terminusCurrently
close
to
500
families
have
thus
been
identified
ascarriers of a THRB gene abnormality and close to 200 different
mutations have been identified (the same mutation may becarried by several different families) [1]As
of
now
there
are
8
known
different
mutations
affecting
theTHRA gene in patients with RTHa (table III ) As with THRB theyare located in the ligand-binding domain (1047297 gure
2) They alsoinvolve
point
mutations
(missense
or
nonsense)
or
abnormali-ties (insertion or deletion of a nucleotide) that result in modifi-cation of the reading frame thus causing a truncated receptorAs with RTHb point mutations seem to be predominant (6 out of8
times)
These
were
de
novo
mutations
in
6
patients
In4 patients the abnormality occurred through autosomal domi-nant transmission by an affected parent (father or mother)Contrary
to
isoforms
TRb1 and
TRb2
which
differ
on
their
N -
terminus
the
main
isoforms
produced
from
the
THRA
geneTRa1
and
TRa2
differ
on
their
C -terminus
They
share
a
commonprotein sequence up until the 360th amino acid the sequencesthen
diverge
resulting
in
a
functional
LBD
for
TRa1
and
an
LBDthat is incapable of binding T3 for TRa2 Six of the eight abnor-malities detected are located in the part of the gene concerningonly
TRa1 [14ndash161920] the
two
others
concern
the
commonsequence between TRa1 and TRa2 [1721] Several of themutations
identified
in
the
THRA
gene
in
cases
of
RTHa
werealso identified in the THRB gene in cases of RTHb A263V (THRA)
Figure
1
The
main
isoforms
produced
by
the
THRB
gene
and
themutations
described
in
the
b
form
of
resistance
to
thyroid
hormonesThe isoforms TRb1 and TRb2 are functional receptors capable of binding DNA and T3
and
influencing under the control of the latter the expression of target genes The
mutations found in RTHb are concentrated in the T3 binding domain (E)and thehinge
domain (D) which separates it from the DNA-binding domain (C) and theN -terminus
transactivation domain (AB) Theyare present in the common sequenceof isoforms
TRb1
and TRb2 Three areas are particularly sensitive to mutations (hot spots) and
are foundbetween aminoacids234and 282 ( 1) 309 and 353 ( 2) and 426 and
460 ( 3 numbering in 461 amino acids of the TRb1
receptor)
TRa
receptor mutations extend the spectrum of syndromes of reduced sensitivity tothyroid hormone ENDOCRINOLOGIE
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and
A317V
(THRB) [17] R384C
and
R438C
[1926] C392X
andC446X
mutations
[2027] Modification
of
the
reading
framefrom amino acid 382 in TRa1 (due to the insertion of a nucleo-tide base in the
THRA gene) [15] has also been reported in the
equivalent
residue
of
TRb1TRb2 (insertions
of
several
bases
inthe THRB gene) [28] although the erroneous consecutivesequence is not the same For the other
THRA gene mutations
with
no
strict
equivalent
in
the
THRB
gene
similar
mutationshave been described either resulting in another substitution oroccurring in a neighbouring residue One notable exceptionhowever is the N359Y mutation [21] which has no strictequivalent
and
in
which
the
corresponding
amino
acid
in
theTRb1TRb2 sequence is not in one of the three known hotspots (a partial explanation for this may lie in the distinctivefeatures
of
the
phenotype
associated
with
this
mutation
see
below)
In
any
case
comparison
of
the a
and b
forms
of
RTH
foridentical
or
equivalent
mutations
enables
the
respective
rolesof the different receptors to be specified In general then the b
receptors
seem
to
be
clearly
involved
in
the
hypothalamic-pituitary feedback loop while the a receptors are more involvedin the peripheral effects of THSeveral
TRa1 mutants
have
been
examined
in
functional
stud-ies Their common points include their incapability to induce theexpression
of
target
genes
and
their
dominant
negative
repres-sor activity over the normal TRa1 receptor [14ndash172129] When
it
was
evaluated
the
affinity
for
T3
was
reduced
[161721]Moreover
the
dominant
negative
activity
seems
to
be
exertedon the TRb1 receptor [152129] The still small number ofreported cases does not enable the formulation of genotypendashphenotype
correlations
For
example
only
two
mutations
affectboth TRa1 and TRa2 While the A263V mutation does not resultin a phenotype different from that observed for mutations thatonly
affect
TRa1 [17]the
phenotype
associated
with
the
N359Ymutation is particular due to the incidence (coincidental) of amarked malformation syndrome and hypercalcemia from para-thyroid hyperplasia and even to the absence of constipation andintellectual
deficit
(though
this
absence
has
also
been
observedin other cases) [21] Whether other isoforms produced from theTHRA
gene (TRa3 p43 P30 TRD1 and TRD2) are implicated inthe
phenotype
also
deserves
to
be
explored
[21] Although
this
needs
to
be
substantiated
with
subsequent
clinical
cases
thereis
a
tendency
for
more
serious
forms
to
exist
with
the
mutationoccurring early in the sequence and resulting in truncation Themost
significant
intellectual
deficit
(IQ
of
22)
was
described
forthe mutation involving the 18 amino acid deletion of TRa1 [20]Conversely patients with normal IQs are carriers of missensepoint
mutations
that
only
substitute
one
amino
acid
for
another[2021] In RTHb the severe forms are also often related toTRb1TRb2
truncations
[28] It
is
likely
that
truncations
(result-ing in the lack of C -terminal helix 12) induce more severe
TABLE IIIDescription
of
the
known
mutations
in
THRA
gene
(encoding
the
thyroid
hormone
receptor
TRa1)
in
patients
with
the a
syndrome
of
resistance
to
thyroid
hormone
Protein
mutation1
Number of
involvedfamilies
Number of
involvedpatients
THRA gene mutations2 Type of protein
mutation
Consequences for protein
functions
Involved
isoforms
References
A263V 1 3 Single base substitution (CxxxxT) Missense Single aminoacid substitution TRa1TRa2
[17]
N359Y 1 1 Single base substitution (C1075G) Missense Single aminoacid substitution TRa1TRa2
[21]
A382fs388X 1 1 Single base deletion(1144delG)
Frameshift Wrong sequence from A382then premature truncation at
position 388
TRa1 [16]
R384C 1 1 Single base substitution (C1150 T) Missense Single aminoacid substitution TRa1 [19]
C392X 1 1 Single base substitution (C1176A) No-sense Premature truncation atposition C392
TRa1 [20]
F397fs406X 1 2 Single base insertion(1144insT) Frameshift
Wrong sequence from F397then premature truncation atposition 406
TRa1 [1518]
P398R 1 1 Single base substitution (C1150 T) Missense Single aminoacid substitution TRa1 [20]
E403X 3 4 Single base substitution (C1176A) No-sense Premature truncation atposition E403
TRa1 [1420]
1The numbering is based on the TRa1 protein sequence (common to the TRa2 sequence until the amicoacid 360)2All mutations are located in exon 9 of the THRA gene (last exon of TRa1 and the secondlast for TRa2)
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Figure 2
The
main
isoforms
produced
by
the
THRA
gene
and
the
mutations
described
in
the
a
form
of
resistance
to
thyroid
hormonesIsoform TRa1 isa functional receptor capable of binding DNA and T3 and influencingunder thecontrolof thelatter theexpression of target genes Isoform TRa2
is incapable of
binding thehormoneand behaves like a weak dominant negative inhibitor of the T3 functionalreceptorsFor now themutations found in RTHa rein the T3 binding domain (E)
while
thehinge domain(D) theDNA-binding domain (C)and theN -terminus transactivation domain (AB) arespared Themutationsconcern the commonsequence of thetwo
isoforms TRa1andTRa2 oronlyaffectthe C -terminussequence of TRa1 (numbering in410 amino acids ofthe TRa1 receptor) Thepoint mutations arerepresentedby a star and
the
frameshift mutations by a star at the level of the first mutated amino acid fol lowed by a blue box representing the modified sequence
The four mutations introduced in the THRA gene to try to generate murine models of the a form of resistance to thyroid hormones are also indicated in italic font (R384C
P394fs406X P398H and L400R) The numbering for the murine isoform TRa1
is the same as for the human isoform
TRa receptor mutations extend the spectrum of syndromes of reduced sensitivity tothyroid hormone ENDOCRINOLOGIE
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phenotype by profoundly affecting TR function through totalinability
to
interact
with
coactivatorsThe genotypendashphenotype correlations may in fact need to beinvestigatedin
animal
modelsMicewith
complete
inactivationof the THRA andor
THRB genes have been reported [11] but
may not represent the most relevant models as the absence ofa receptor does nothave the same consequences as the expres-sion
of
an
abnormal receptor
The comparison
is
more
logical inanimal
models
with
an
artificially
introduced
mutation For theTHRA
gene thereare fourdifferentmodels available that are allbased
on
a
mutation
of
the hormone-binding domain in
onlythe TRa1 receptor (1047297 gure 2 no model with mutation affectingTRa1
and TRa2)
One model
introduced
in
TRa1 the PV
muta-tion [13] which was identified in a patientwith RTHb (insertionof
several
nucleotides
with
modification of
the reading
frame)[30]
while
the others
introduce
point
mutations
R384C
[29](corresponding exactly to a
THRA mutation in a patient with
RTHa
[19])
L400R
[31]
and P398H
[32] These models
providephenotypic data that are complementary to those reported inhuman cases The growth retardation with impairment in ossi-fication is consistent in all animals [132931ndash34] The role ofTRa1
in
the development
of
chondrocytes
is probably a
deter-mining factor
as
the
elective introduction
of
the
L400R
muta-tion in the chondrocytes is sufficient to induce the phenotype[35]
The severity
of
the bone phenotype however
is
variabledepending on the models The bone phenotype of the R384Cmutation for instance was observed in young mice and dis-appeared in
the adultmice
[29]
In humans this
mutationwasreported in
a
girl though
it
is
only
known that
she
was
a
carrierof a familial form of autism without other information on herphenotype It is interesting to observe that the R384C mice hadsignificant psychomotor
disorders
with
anxiety memoryimpairment and depression (which are possible even fre-quent manifestations of autism) [3637] Cerebellar ataxiawas
also
observed
in
another
model
[31]
which
is
somewhatsimilar to the clumsiness and awkwardness described in thegait or the handling of objects in several patients with RTHa[141617] In animals these psychoneuromotor disorders arerelated
to impairment
of
neurogenesis
in
the hippocampus(lack of certain GABAergic interneurons) [38] and diminishpartially with levothyroxine [3638] This reduction on treat-ment
is not
observed
for the
bone
phenotype [39] as
was
also
reported in
humans Another
common
point of
the animalmodels
with
TRa1 mutations
is the
near-normality
of
TH
serumlevels On the other hand TSH has been found to be high inseveral
models
[1332]
as
opposed to its usual observed nor-mality in patients with RTHa (high-normal values in one case[16]) The T4T3 ratio and the reverse T3 (rT3) found to be lowin
patients with
RTHa
are
considered
an
indication of
theperipheral metabolism of TH Interestingly high levels of type1
deiodinase
(responsible for the conversion
of
T4
into
T3 andfor the clearance of rT3)have been measured in the liver of one
of the murine models [13] Normal levels were however
detected
in
another [31]Investigations of murine models found bradycardia [293132]which
was
rather
mild
but
accompanied
by
inadaptation
tostress [40] Bradycardia was reported in patients with RTHa
[141617] but the rare functional heart explorations that weredone did not demonstrate serious abnormalities [16] Bradycar-dia
is
probably
the
result
of
the
direct
effect
of
TH
on
themyocardium
(known
target
tissue
of
TH
expressing
ratherTRa1) abnormalities of calcium flux and contractility wereobserved
in
one
model
[41] However
there
is
probably
anothermechanism involved namely deregulation of the autonomicnervous
system
due
to
abnormal
brain
development
[4042]The same mechanism (lack of cerebral control on the autonomicnervous
system)
has
been
suggested
as
an
explanation
forthermogenesis
abnormalities
These
abnormalities
have
notbeen actually reported (not explored) in patients with RTHa
A
reduction
in
body
temperature
andor
a
cold
intolerance
wasdescribed in two murine models [3132] Dysfunction of thebrown fat is suspected related to deregulation of the autonomicnervous system caused by abnormal brain development [38]Increased
vasodilatation
again
related
to
the
autonomic
ner-vous
system
was
supposedly
also
observed
in
one
of
the
mo-dels with abnormal thermogenesis [43]One
patient
with
RTHa
had
weight
loss
(occurring
in
childhoodand continuing in adulthood) [21] while the other patients hadnormal or increased weight [15ndash18] One murine model exhib-ited
overweight
(without
increased
food
intake)
hepatic
stea-tosis
and
insulin
resistance
[32] but
a
controversy
exists
aboutthe real responsibility of THRA mutation Two others models hadhyperphagia without weight gain resistance to tube-feedingmild
adiposity
due
to
impairment
of
adipogenesis
and
low
liverconcentrations of lipids [44ndash46] The same mechanism aninteraction with PPARg has been suggested in both of thesecontrary
situations
[4547]
ConclusionsTowards the end of the 1980s the first descriptions of abnor-malities of the
THRB gene in patients with RTHb generated a
very
large
number
of
questions
about
the
possibility
of
muta-tions
in
the
THRA
gene
Answers
have
arrived
more
than
20
yearslater with the description of clinical phenotypes that are quite
particular
abnormalities
suggestive
of
mild
untreated
congeni-tal hypothyroidism in conjunction with thyroid function teststhat are more or less normal and therefore discordant For themoment
suggestive
symptoms
are
short
stature
hypothyroid-ism-like
facial
shape
and
low
T4T3
ratio
It
is
worthy
to
notethat
the
whole
exome
database
(httpexacbroadinstituteorg) contains 68
THRA missense or frameshift mutations with
most
of
them
predicted
to
alter
TRa1 function
It
is
thereforelikely that several patients in the general population haveundiagnosed RTHa with milder phenotype As in RTHb it is
V Vlaeminck-Guillem S Espiard F Flamant J-LWeacutemeau
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the discordance between the clinical and the laboratory datathat
should
stand
out
for
the
clinician
The
identification
ofpatients with authenticated abnormalities of the
THRA gene
is
essential
for
improving
the
definition
of
the
clinical
spectrumof RTHa and more generally of all RTH and syndromes of
reduced sensitivity to thyroid hormones This improved pheno-typic definition will enable genotypendashphenotype correlations tobe
formulated
and
perhaps
the
development
of
therapeuticguidelines
The
reported
cases
show
that
the
administrationof TH in patients with RTHa does not improve all the symptomsprobably
because
the
therapeutic
management
occurs
too
latefor certain abnormalities that have already become definitivelyestablished
andor
because
the
tissue
resistance
is
too
severeThe extreme dependence for TH during the brain development isa
clear
example
of
the
need
for
early
treatment
The
significance
of this seems to depend partially on the nature of the underlyinggenetic
abnormality
The
different
murine
models
with
diversegenetic abnormalities may thus be valuable tools for testing thetherapeutic
approaches
Assuming
that
the
resistance
is
toosevere to be managed by hormonal treatment identification
of the major role in animals of the interaction of mutated TRa1with corepressors such as NCoR [48] was crucial Indeed it ledto
the
demonstration
of
the
partial
reversal
of
the
abnormalTHRA
gene
phenotype
through
the
coexpression
of
a
mutantNCoR unable to interact with the TRs [49] and through theadministration
of
an
inhibitor
of
the
corepressors-associatedhistone deacetylase activity [50]
Disclosure of interest the authors declare that they have no conflicts ofinterest concerning this article
References[1] Dumitrescu AM Refetoff S The syndromes
of reduced sensitivity to thyroid hormoneBiochim Biophys Acta 201318303987ndash 4003
[2] Refetoff S DeWind LT
DeGroot LJ Familialsyndrome combining deaf-mutism stuppledepiphyses goiter and abnormally high PBIpossible target organ refractoriness to thyroidhormone J Clin Endocrinol Metab196727279ndash 94
[3] Sakurai A TakedaK Ain K Ceccarelli P NakaiA Seino S et al Generalized resistance tothyroid hormone associated with a mutationin the ligand-binding domain of the humanthyroid hormone receptor beta Proc Nat l
Acad Sci U S A 1989868977ndash 81
[4] Vlaeminck-Guillem V Margotat A Torresani J DHerbomez M Decoulx M Wemeau JLResistance to thyroid hormone in a familywith no TRbeta gene anomaly pathogenichypotheses Ann Endocrinol (Paris)200061149ndash 94
[5] Weiss RE
Hayashi Y
Nagaya T
Petty KJMurata Y Tunca H et al Dominant inheri-tance of resistance to thyroid hormone notlinked to defects in the thyroid hormonereceptor alpha or beta genes may be dueto a defective cofactor J Clin EndocrinolMetab1996814196ndash 203
[6] Pohlenz J Weiss RE
Macchia PE Pannain SLau IT Ho H et al Five new families with
resistance to thyroid hormone not caused bymutations in the thyroid hormone receptorbeta gene J Clin Endocrinol Metab1999843919ndash 28
[7] DumitrescuAM Liao XH Abdullah MS Lado-Abeal J Majed FA Moeller LC et al Muta-tions in SECISBP2 result in abnormal thyroidhormone metabolism Nat Genet2005371247ndash 52
[8] Dumitrescu AM Liao XH Best TB Brock-mann K Refetoff S A novel syndromecombining thyroid and neurological
abnormalities is associated with mutationsin a monocarboxylate transporter gene Am J Hum Genet 200474168ndash 75
[9] Friesema EC Grueters A
Biebermann HKrude H von Moers A Reeser M et alAssociation between mutations in a thyroidhormone transporter and
severe X-linked psy-chomotor retardation Lancet 20043641435ndash 7
[10] Refetoff S Bassett JH
Beck-Peccoz P Bernal JBrent G Chatterjee K et al Classificationandproposednomenclaturefor inheriteddefects ofthyroid hormone action cell transport andmetabolism Eur Thyroid J 201437ndash 9
[11] Vlaeminck-Guillem V Wemeau JL
Physiolo-gie et physiopathologie des reacutecepteurs thyr-oiumldiens lapport des modegraveles murins AnnEndocrinol (Paris) 200061440ndash 51
[12] Wikstrom L Johansson C Salto C Barlow CCampos Barros A Baas F et al Abnormalheart rate and body temperature in micelacking thyroid hormone receptor alpha 1EMBO J 199817455ndash 61
[13] Kaneshige M Suzuki H Kaneshige K Cheng J Wimbrow H Barlow C et al A targeteddominant negative mutation of the thyroidhormone alpha 1 receptor causes increasedmortality infertility and dwarfism in miceProc Natl Acad Sci U S A 20019815095ndash 100
[14] Bochukova E Schoenmakers N Agostini M
Schoenmakers E RajanayagamO Keogh JMet al A mutation in the thyroid hormonereceptor alpha gene N Engl J Med2012366243ndash 9
[15] van Mullem A van Heerebeek R Chrysis DVisser E Medici M Andrikoula M et alClinical phenotype and mutant TRalpha1 NEngl J Med 20123661451ndash 3
[16] Moran C
Schoenmakers N Agostini MSchoenmakers E Offiah A
Kydd
A et alAn adult female with resistance to thyroidhormone mediated by defective thyroid
hormone receptor alpha J Cl in EndocrinolMetab 2013984254ndash 61
[17] Moran C Agostini M Visser WE Schoen-makers E SchoenmakersN Offiah AC etalResistance to thyroid hormone caused by amutation in thyroid hormone receptor (TR)alpha1 and
TRalpha2 clinical biochemicaland genetic analyses
of three
related patientsLancet Diabet Endocrinol 20142619ndash 26
[18] van Mullem AA Chrysis D Eythimiadou AChroni E Tsatsoulis A de Rijke YB et alClinical phenotype of a new type of thyroidhormone resistance caused by a mutation ofthe TRalpha1 receptor consequences of LT4
treatment J Clin Endocrinol Metab2013983029ndash 38
[19] Yuen RK Thiruvahindrapuram B Merico DWalker S Tammimies K Hoang N et alWhole-genome sequencing of quartetfamilies with autism spectrum disorder NatMed 201521185ndash 91
[20] Tylki-Szymanska A Acuna-Hidalgo R Kra- jewska-Walasek M Lecka-Ambroziak ASteehouwer M Gi lissen C et al Thyroidhormone resistance syndrome due to muta-tions in the thyroid hormone receptor alphagene (THRA) J Med Genet 201552312ndash 6
[21] Espiard S Savagner F
Flamant F
Vlaeminck-Guillem V Guyot R Munier M
et al A novelmutation in THRA gene associated with an
atypical phenotype of resistance to thyroidhormone J Clin Endocrinol Metab 2015 jc20151120
[22] Faivre L Cormier-Daire V GenevieveD PintoG Goulet O
Munnich A
et al A novelsyndrome with dwarfism poorly muscledbuild absent clavicles humeroradial fusionslender bones oligodactyly and micro-gnathia Clin Dysmorphol 200110181ndash 4
[23] Mundlos S Cleidocranial dysplasia clinicaland molecular genetics J Med Genet199936177ndash 82
TRa receptor mutations extend the spectrum of syndromes of reduced sensitivity tothyroid hormone ENDOCRINOLOGIE
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[24] Mundlos S Otto F
Mundlos C Mulliken JBAylsworth AS Albright S et a l Mutat ionsinvolving the transcription factor CBFA1
causecleidocranial dysplasia Cell 199789773ndash 9
[25] Margotat A
Sarkissian G Malezet-Desmou-lins C Peyrol N Vlaeminck Guillem V
Wemeau JL
et al Ident if ication of eightnew mutations in the c-erbAB gene ofpatients with resistance to thyroid hormoneAnn Endocrinol 200162220ndash 5
[26] Adams M Matthews C Coll ingwood TNToneY
Beck-Peccoz P ChatterjeeKK Geneticanalysis of 29 kindreds with generalized andpituitary resistance to thyroid hormone Iden-tification of thirteen novel mutations in thethyroid hormone receptor beta gene J ClinInvest 199494506ndash 15
[27] Groenhout EG Dorin RI Generalized thyroidhormone resistance due to a deletion of thecarboxy terminus of the c-erbA beta receptorMol Cell Endocrinol 19949981ndash 8
[28] Wu SY CohenRN SimsekE Senses DA Yar
NE Grasberger H et al A novel thyroidhormone receptor-beta mutation that failsto bind nuclear receptor corepressor in apatient as an apparent cause of severe pre-dominantly pituitary resistance to thyroid hor-mone J Clin Endocrinol Metab 2006911887ndash 95
[29] Tinnikov A Nordstrom K Thoren P Kindblom JM Malin S Rozell B et al Retardation ofpost-natal development caused by a nega-tively acting thyroid hormone receptoralpha1 EMBO J 2002215079ndash 87
[30] Parrilla R
Mixson AJ McPherson JA
McClas-key JH Weintraub BD Characterization ofseven novel mutations of the c-erbA betagene in unrelated kindreds with generalizedthyroidhormone resistance Evidence for twohot spot regions of the l igand bindingdomain J Clin Invest 1991882123ndash 30
[31] Quignodon L VincentS Winter H Samarut JFlamant F A point mutation in the
activationfunction2 domainof thyroidhormonereceptoralpha1 expressed after CRE-mediated recom-bination partially recapitulates hypothyroid-ism Mol Endocrinol 2007212350ndash 60
[32] Liu YY
Schultz JJ
Brent GA A thyroidhormone receptor alpha gene mutation
(P398H) is associated with visceral adiposityand impaired catecholamine-stimulated lipo-lysis in mice J Biol Chem 200327838913ndash 20
[33] OShea PJ Bassett JH ChengSY Williams GRCharacterization of skeletal phenotypes ofTRalpha1 and TRbeta mutant mice implica-
tions for tissue thyroid status and T3 targetgene expression Nucl Recept Signal 20064e011
[34] OShea PJ Bassett JH Sriskantharajah S YingH Cheng SY Williams GR Contrasting ske-leta l phenotypes in mice with an identicalmutation targeted to thyroid hormone recep-tor alpha1 or beta Mol Endocrinol2005193045ndash 59
[35] Desjardin C
Charles C
Benoist-Lasselin CRiviere J Gilles M Chassande O et alChondrocytes play a major role in the stimu-lation of bone growth by thyroid hormoneEndocrinology 20141553123ndash 35
[36] Venero C Guadano-Ferraz A Herrero AINordstrom K Manzano J de Escobar GM
et al Anxiety memory impairmentand loco-motor dysfunction caused by a mutant thyr-oid hormone receptor alpha1 can beameliorated by T3 treatment Genes Dev2005192152ndash 63
[37] Pilhatsch M
Winter C
Nordstrom K Venn-strom B Bauer M
Juckel G Increaseddepressive behaviour in mice harboring themutant thyroid hormone receptor alpha 1Behav Brain Res 2010214187ndash 92
[38] Kapoor R
van Hogerlinden M
Wallis KGhosh H Nordstrom K Vennstrom Bet al Unliganded thyroid hormone receptoralpha1 impairs adult hippocampal neurogen-esis FASEB J 2010244793ndash 805
[39] Bassett JH Boyde A Zikmund T Evans HCroucher PI
Zhu X
et al
Thyroid hormonereceptor alpha mutation causes a severe
andthyroxine-resistant skeletaldysplasiain femalemice Endocrinology 20141553699ndash 712
[40] Mittag J Davis B Vujovic M Arner AVennstromB Adaptations of theautonomousnervous system controlling heart rate areimpairedby amutant thyroid hormone recep-tor-alpha1 Endocrinology 20101512388ndash 95
[41] Tavi P Sjogren M Lunde PK Zhang SJAbbate F
Vennstrom B et al Impaired
Ca2+ handling and contraction in cardiomyo-cytes from mice with a dominant negativethyroid hormone receptor alpha1 J Mol CellCardiol 200538655ndash 63
[42] Mittag J Lyons DJ Sall strom J Vujovic MDudazy-Gralla S Warner A
et al Thyroid
hormone is required for hypothalamic neu-rons regulating cardiovascular functions J ClinInvest 2013123509ndash 16
[43] Warner A RahmanA Solsjo P Gottschling KDavis B Vennstrom B et al Inappropriateheatdissipation ignitesbrown fat thermogen-esis in mice with a mutant thyroid hormonereceptor alpha1 Proc Natl Acad Sci U S A201311016241ndash 46
[44] SjogrenM AlkemadeA
MittagJ
NordstromK KatzA Rozell B etal Hypermetabolisminmice caused by the central action of an unli-ganded thyroid hormone receptor alpha1EMBO J 2007264535ndash 45
[45] Ying H Araki O Furuya F Kato Y Cheng SYImpaired adipogenesis caused by a mutated
thyroid hormone alpha1 receptor Mol CellBiol 2007272359ndash 71
[46] Araki O
Ying H Zhu XG Willingham MCChengSY Distinct dysregulationof lipid meta-bolismbyunligandedthyroid hormone recep-tor isoforms Mol Endocrinol 200923308ndash 15
[47] Liu YY
Heymann RS Moatamed F
Schultz JJSobel D Brent GA A mutant thyroid hor-mone receptor alphaantagonizesperoxisomeproliferator-activated receptor alpha signalingin vivo and impairs fatty acid oxidation Endo-crinology 20071481206ndash 17
[48] Fozzatt i L Lu C
Kim DW Cheng SY Differ-ential recruitment of nuclear coregulatorsdirects the isoform-dependent action ofmutant thyroid hormonereceptorsMol Endo-crinol 201125908
ndash 21
[49] Fozzatti
L Kim
DW
ParkJW Willingham
MCHollenberg AN Cheng SY Nuclear receptorcorepresso r (NCOR1) regulates in vivoactions ofa mutated
thyroid
hormone recep-tor alpha Proc Natl
Acad
Sci U S A20131107850ndash 5
[50] Kim DW ParkJW
Willingham MC Cheng SYA histone deacetylase inhibitor improveshypothyroidism caused by a TRalpha1mutant Hum Mol Genet 2014232651ndash 64
V Vlaeminck-Guillem S Espiard F Flamant J-LWeacutemeau
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constipation
The
dysmorphic
syndrome
combines
small
staturedecreased
limb
length
with
a
trunk
that
is
of
rather
normal
size(even elongated in the thoracic portion) and multiple facialanomalies
that
may
include
macrocephaly
(the
need
for
acaesarean section was reported several times) rather coarsefeatures hypertelorism of the eyeballs a short and wide nosemicrognathism
delayed
tooth
eruption
a
short
neck
or
evenmacroglossia The decreased stature is related to growth retar-dation
(sometimes
detected
in
utero)
and
can
even
border
ondwarfism [21] The feet and hands may be enlarged
Malformations
have
also
been
reported
such
as
congenitalhip
dislocation
or
coxa
valga
One
described
case
included
aunique malformation syndrome (sufficiently significant to pro-voke
a
separate
publication
more
than
10
years
before
thediscovery of the molecular substratum [22]) with bilateralagenesis of the clavicles unilateral humero-radial synostosiselbow
dislocation
syndactyly
of
the
4th
and
5th
toes
absence
ofthe 12th rib scoliosis and hip dysplasia [21] (presentationsuggestive
of
cleidocranial
dysostosis
[2324]) With
regard
topsychomotor status there have been reports of abnormalities in
TABLE IClinical
phenotype
of
the
14
published
cases
of
resistance
to
thyroid
hormone
due
to
a
defective
TRa
receptor
Gender Females n = 9Males n = 5
Age at the molecular diagnosis Childrenteenagers 6 to 18 years (n = 7)Adults 25 to 60 years (n = 7)
Origin European Caucasian n = 13North-American n = 1
Dysmorphic syndrome
Figure
Growth retardation n = 10Height Small in 9 patients Normal in 3 patients
Weight Thinness n = 1Ideal weight n = 3
Overweight n = 1Obesity n = 3
Long thorax n = 6Short limbs n = 7 No in 3 other patients
Face dysmorphism
Macrocephaly n = 11Coarse facial features n = 6 (no in a
7th patient)
Eye hypertelorism n = 7Flat nasal bridge upturned nose n = 8Short neck n = 4 (no in a 5th patient)
Micrognathia n = 2Macroglossia n = 5 (no in a 6th patient)
Delayed tooth eruption n = 2Malformations n = 5Ends of the limbs n = 3 (congenital dislocation coxa valga)Hip n = 1Cleidocranial dysplasia n = 5
Cognition disorders
Psychomotor disorders Yes n = 7
No n = 7Cognitive defect No defect n = 2
Mild defect n = 7Moderate to severe defect n = 4
Bradycardia n = 5 (no in 3 other patients)
Constipation n = 11 (no in a 12th patient)
Hypercholesterolemia n = 11 (no in a 12th patient)
Anemia Microcytic n = 10Macrocytic n = 3
TRa receptor mutations extend the spectrum of syndromes of reduced sensitivity tothyroid hormone ENDOCRINOLOGIE
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coordination learning to walk and reading Mild to severeintellectual
deficit
has
often
been
reported
but
is
not
systematic[2021] Constipation is nearly constant with an early appear-ance
in
childhood
one
case
of
diarrhoea
occurring
late
inadulthood was described [21] Bradycardia another sign sug-
gestive of hypothyroidism is sometimes reported [141617]Overweight is also possible particularly in adults [15ndash18] Bodytemperature
appears
normal
[1518] whereas
the
baselinemetabolism
is
decreased
[14161721] Finally
cases
of
carpaltunnel syndrome have been reported [17] as is sometimesdescribed
in
association
with
myxoedema
of
hypothyroidismThe routine laboratory tests are normal except for anaemiawhich
is
consistently
present
in
all
clinical
descriptions
but
israther moderate It is usually normocytic though sometimesmacrocytic
[1721]) Hypercholesterolemia
may
also
occur[15ndash1820] Insulin-like
growth
factor
1
may
be
low
in
childrenand adolescents patients [14ndash1618]
Radiological
exams
are
done
to
investigate
potential
malforma-tion syndromes [2021] Skull X-rays in children confirm macro-cephaly and show delay of ossification in the fontanels and thepersistence of wormian bones (which reflect ossification abnor-malities)
[14]
Ossification
delay
is
also
evidenced
by
epiphysealdysgenesis
(femoral
heads)
[141518]
and
by
delayed
boneage An ovoid appearance of the vertebrae is possible [20] Inadults
X-rays
again
show
macrocephaly
with
thickening
of
theskull vault (occipital in particular) and enlargement of the frontalbone [1617] Cortical bone thickening has also been describedon
the
long
bones
of
the
limbs
[16] Osteodensitometric
meas-urements
in
adults
are
usually
normal
[16ndash1821]The signs of hypothyroidism that are typically found lead logi-cally to an investigation of thyroid function tests Though pro-viding
reassurance
when
values
are
normal
or
low
normal
they
must attract attention when there is a discrepancy with the
clinical
presentation
It
is
this
dissociation
between
normallaboratory values and the more or less pronounced signs ofhypothyroidism
(including
the
dysmorphic
syndrome)
thatshould suggest the diagnosis of RTHa It is the opposite condi-
tion of RTHb where the symptoms of hyperthyroidism are ratherminimal in association with laboratory indications of hyperthy-roidism
(table
II )
In
this
respect
it
can
be
seen
that
thedissociation
between
the
clinical
and
laboratory
observationsis a key element of RTH both in the alpha and the beta formsThe
thyroid
hormone
values
both
in
their
free
and
total
formsare more or less normal There is a tendency however for T4 tobe
slightly
low
and
T3
slightly
high
As
a
result
there
is
adecreased T4T3 ratio which was the only consistent factorin
all
the
published
cases
The
TSH
is
normal
(though
low
insome
cases)
It
should
be
noted
that
neonatal
screening
forhypothyroidism which is based on TSH cannot identify RTHa
Several
patients
received
treatment
with
levothyroxine
some-times even before the clinical or specific molecular diagnosisThe clinical effects are inconclusive particularly because cogni-tive disorders and dysmorphic syndrome are often alreadyestablished
and
definitive
[14] Benefits
can
be
seen
for
brady-cardia
energy
levels
bowel
function
and
carpal
tunnel
syn-drome [1617] There is usually an increase in the concentrationsof
thyroid
hormones
and
a
quick
and
predictable
suppression
ofTSH which reflects the successful adaptation of the hypotha-lamic-pituitary axis Improvement of the other abnormal labo-ratory
values
(blood
cholesterol
anaemia)
is
not
constant
Molecular bases of RTHa
The functional thyroid receptors are the isoforms TRb1 TRb2andTRa1 They are present in the nucleus of the target cells as
TABLE IIClinical
and
biological
phenotypes
of
the
a
and
b
syndromes
of
resistance
to
thyroid
hormones
RTHa RTHb
Involved gene THRA THRB
Involved receptors TRa11 TRb1TRb2
Clinical phenotype Mild hypothyroidism(short height dysmorphic syndrom)
Mild hyperthyroidism (tachycardia nervousness)
Goiter No Yes
fT3 High-normal High
fT4 Low normal High
T4T3 ratio Low Low
TSH Normal or low High
1Some mutations of the THRA gene also involve non-functional isoforms such as the TRa2 protein
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dimers They are capable of binding on theDNA specific targetsequences (thyroid
hormone response elements
or
TREs)which are located in the regulatory sequences (promotersenhancers) of
the target
genes Like the other
nuclear
recep-tors they in fact behave like ligand-inducible transcription
factors In the absence of hormones and through interactionwith cofactors that repress their transcriptional activity (core-pressors) the
TR reduces
the expression
of
the target
genesLigandbindingenables the TR to releasecorepressors to
recruitactivating partners of transcription (coactivators) and to theninduce
the transcription
of
the target
genes
To
fulfil all
thesefunctions (DNA-binding hormone binding transactivationactivity) the TRs are
organized
into
modules an
N -terminustransactivation domain a DNA-binding domain (DBD) a hingedomain
and a
ligand-binding domain
(LBD) Organized
as
asuccession
of
12
helices this last domain
has on
its C -terminusthe transactivation domain the activity of which is exerted in
the presence
of
the ligand
Indeedmodifications
of
the recep-tor structure occur during hormone binding and involve moreparticularly the 12th helix (H12) which includes the last C -terminus amino acidsIn
the
b
form
of
RTH
the
abnormality
is
carried
by
the
THRB
gene
The
mutations
are
essentially
distributed
over
the
LBD
andthe hinge domain (they do not affect the DNA-binding domainor
the
N -terminus
transactivation
domain)
(1047297 gure
1)
Threeregions rich in cytosine and guanine clusters (CpG islands)are particularly subject to genetic abnormalities (hot spots)[1]
even
though
some
mutations
have
been
reported
outsideof
these
hot
spots
[25] The
two functional
isoforms
producedfrom the THRB gene differing at their N -terminus (TRb1 andTRb2) are both concerned by these
C -terminus abnormalitiesDNA
binding
is
preserved
and
classically
the
mutated
receptorshave a reduced or absence of affinity for T3 They can also havenormal affinity for T3 but a constitutional inability to interactwith
coactivators
[1]
The
phenotype
is
expressed
while
a
singlecopy of the gene is usually involved (heterozygous mutation)The explanation lies in a dominant negative activity exerted bythe mutant receptors on the still functional isoforms By dime-rizing
with
them
they
prevent
the
release
of
the
corepressorsthe recruitment of the coactivators and finally transcriptionalactivity In 90 of cases the identified mutations are missensepoint
mutations
(a
nucleotide
base
is
changed
into
another
resulting
in
an
amino
acid
substitution
on
the
protein
[1])Sometimes
the
point
mutation
is
a
nonsense
mutation
(whichstops protein translation) it may involve the deletion or inser-tion
of
a
nucleotide
base
which
then
leads
to
a
modification
ofthe reading frame and translation of the genetic message intoan erroneous protein message In the case of nonsense muta-tions
or
modifications
of
the
reading
frame
the
affected
recep-tors are truncated on a more or less long part of their
C -terminusCurrently
close
to
500
families
have
thus
been
identified
ascarriers of a THRB gene abnormality and close to 200 different
mutations have been identified (the same mutation may becarried by several different families) [1]As
of
now
there
are
8
known
different
mutations
affecting
theTHRA gene in patients with RTHa (table III ) As with THRB theyare located in the ligand-binding domain (1047297 gure
2) They alsoinvolve
point
mutations
(missense
or
nonsense)
or
abnormali-ties (insertion or deletion of a nucleotide) that result in modifi-cation of the reading frame thus causing a truncated receptorAs with RTHb point mutations seem to be predominant (6 out of8
times)
These
were
de
novo
mutations
in
6
patients
In4 patients the abnormality occurred through autosomal domi-nant transmission by an affected parent (father or mother)Contrary
to
isoforms
TRb1 and
TRb2
which
differ
on
their
N -
terminus
the
main
isoforms
produced
from
the
THRA
geneTRa1
and
TRa2
differ
on
their
C -terminus
They
share
a
commonprotein sequence up until the 360th amino acid the sequencesthen
diverge
resulting
in
a
functional
LBD
for
TRa1
and
an
LBDthat is incapable of binding T3 for TRa2 Six of the eight abnor-malities detected are located in the part of the gene concerningonly
TRa1 [14ndash161920] the
two
others
concern
the
commonsequence between TRa1 and TRa2 [1721] Several of themutations
identified
in
the
THRA
gene
in
cases
of
RTHa
werealso identified in the THRB gene in cases of RTHb A263V (THRA)
Figure
1
The
main
isoforms
produced
by
the
THRB
gene
and
themutations
described
in
the
b
form
of
resistance
to
thyroid
hormonesThe isoforms TRb1 and TRb2 are functional receptors capable of binding DNA and T3
and
influencing under the control of the latter the expression of target genes The
mutations found in RTHb are concentrated in the T3 binding domain (E)and thehinge
domain (D) which separates it from the DNA-binding domain (C) and theN -terminus
transactivation domain (AB) Theyare present in the common sequenceof isoforms
TRb1
and TRb2 Three areas are particularly sensitive to mutations (hot spots) and
are foundbetween aminoacids234and 282 ( 1) 309 and 353 ( 2) and 426 and
460 ( 3 numbering in 461 amino acids of the TRb1
receptor)
TRa
receptor mutations extend the spectrum of syndromes of reduced sensitivity tothyroid hormone ENDOCRINOLOGIE
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and
A317V
(THRB) [17] R384C
and
R438C
[1926] C392X
andC446X
mutations
[2027] Modification
of
the
reading
framefrom amino acid 382 in TRa1 (due to the insertion of a nucleo-tide base in the
THRA gene) [15] has also been reported in the
equivalent
residue
of
TRb1TRb2 (insertions
of
several
bases
inthe THRB gene) [28] although the erroneous consecutivesequence is not the same For the other
THRA gene mutations
with
no
strict
equivalent
in
the
THRB
gene
similar
mutationshave been described either resulting in another substitution oroccurring in a neighbouring residue One notable exceptionhowever is the N359Y mutation [21] which has no strictequivalent
and
in
which
the
corresponding
amino
acid
in
theTRb1TRb2 sequence is not in one of the three known hotspots (a partial explanation for this may lie in the distinctivefeatures
of
the
phenotype
associated
with
this
mutation
see
below)
In
any
case
comparison
of
the a
and b
forms
of
RTH
foridentical
or
equivalent
mutations
enables
the
respective
rolesof the different receptors to be specified In general then the b
receptors
seem
to
be
clearly
involved
in
the
hypothalamic-pituitary feedback loop while the a receptors are more involvedin the peripheral effects of THSeveral
TRa1 mutants
have
been
examined
in
functional
stud-ies Their common points include their incapability to induce theexpression
of
target
genes
and
their
dominant
negative
repres-sor activity over the normal TRa1 receptor [14ndash172129] When
it
was
evaluated
the
affinity
for
T3
was
reduced
[161721]Moreover
the
dominant
negative
activity
seems
to
be
exertedon the TRb1 receptor [152129] The still small number ofreported cases does not enable the formulation of genotypendashphenotype
correlations
For
example
only
two
mutations
affectboth TRa1 and TRa2 While the A263V mutation does not resultin a phenotype different from that observed for mutations thatonly
affect
TRa1 [17]the
phenotype
associated
with
the
N359Ymutation is particular due to the incidence (coincidental) of amarked malformation syndrome and hypercalcemia from para-thyroid hyperplasia and even to the absence of constipation andintellectual
deficit
(though
this
absence
has
also
been
observedin other cases) [21] Whether other isoforms produced from theTHRA
gene (TRa3 p43 P30 TRD1 and TRD2) are implicated inthe
phenotype
also
deserves
to
be
explored
[21] Although
this
needs
to
be
substantiated
with
subsequent
clinical
cases
thereis
a
tendency
for
more
serious
forms
to
exist
with
the
mutationoccurring early in the sequence and resulting in truncation Themost
significant
intellectual
deficit
(IQ
of
22)
was
described
forthe mutation involving the 18 amino acid deletion of TRa1 [20]Conversely patients with normal IQs are carriers of missensepoint
mutations
that
only
substitute
one
amino
acid
for
another[2021] In RTHb the severe forms are also often related toTRb1TRb2
truncations
[28] It
is
likely
that
truncations
(result-ing in the lack of C -terminal helix 12) induce more severe
TABLE IIIDescription
of
the
known
mutations
in
THRA
gene
(encoding
the
thyroid
hormone
receptor
TRa1)
in
patients
with
the a
syndrome
of
resistance
to
thyroid
hormone
Protein
mutation1
Number of
involvedfamilies
Number of
involvedpatients
THRA gene mutations2 Type of protein
mutation
Consequences for protein
functions
Involved
isoforms
References
A263V 1 3 Single base substitution (CxxxxT) Missense Single aminoacid substitution TRa1TRa2
[17]
N359Y 1 1 Single base substitution (C1075G) Missense Single aminoacid substitution TRa1TRa2
[21]
A382fs388X 1 1 Single base deletion(1144delG)
Frameshift Wrong sequence from A382then premature truncation at
position 388
TRa1 [16]
R384C 1 1 Single base substitution (C1150 T) Missense Single aminoacid substitution TRa1 [19]
C392X 1 1 Single base substitution (C1176A) No-sense Premature truncation atposition C392
TRa1 [20]
F397fs406X 1 2 Single base insertion(1144insT) Frameshift
Wrong sequence from F397then premature truncation atposition 406
TRa1 [1518]
P398R 1 1 Single base substitution (C1150 T) Missense Single aminoacid substitution TRa1 [20]
E403X 3 4 Single base substitution (C1176A) No-sense Premature truncation atposition E403
TRa1 [1420]
1The numbering is based on the TRa1 protein sequence (common to the TRa2 sequence until the amicoacid 360)2All mutations are located in exon 9 of the THRA gene (last exon of TRa1 and the secondlast for TRa2)
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Figure 2
The
main
isoforms
produced
by
the
THRA
gene
and
the
mutations
described
in
the
a
form
of
resistance
to
thyroid
hormonesIsoform TRa1 isa functional receptor capable of binding DNA and T3 and influencingunder thecontrolof thelatter theexpression of target genes Isoform TRa2
is incapable of
binding thehormoneand behaves like a weak dominant negative inhibitor of the T3 functionalreceptorsFor now themutations found in RTHa rein the T3 binding domain (E)
while
thehinge domain(D) theDNA-binding domain (C)and theN -terminus transactivation domain (AB) arespared Themutationsconcern the commonsequence of thetwo
isoforms TRa1andTRa2 oronlyaffectthe C -terminussequence of TRa1 (numbering in410 amino acids ofthe TRa1 receptor) Thepoint mutations arerepresentedby a star and
the
frameshift mutations by a star at the level of the first mutated amino acid fol lowed by a blue box representing the modified sequence
The four mutations introduced in the THRA gene to try to generate murine models of the a form of resistance to thyroid hormones are also indicated in italic font (R384C
P394fs406X P398H and L400R) The numbering for the murine isoform TRa1
is the same as for the human isoform
TRa receptor mutations extend the spectrum of syndromes of reduced sensitivity tothyroid hormone ENDOCRINOLOGIE
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phenotype by profoundly affecting TR function through totalinability
to
interact
with
coactivatorsThe genotypendashphenotype correlations may in fact need to beinvestigatedin
animal
modelsMicewith
complete
inactivationof the THRA andor
THRB genes have been reported [11] but
may not represent the most relevant models as the absence ofa receptor does nothave the same consequences as the expres-sion
of
an
abnormal receptor
The comparison
is
more
logical inanimal
models
with
an
artificially
introduced
mutation For theTHRA
gene thereare fourdifferentmodels available that are allbased
on
a
mutation
of
the hormone-binding domain in
onlythe TRa1 receptor (1047297 gure 2 no model with mutation affectingTRa1
and TRa2)
One model
introduced
in
TRa1 the PV
muta-tion [13] which was identified in a patientwith RTHb (insertionof
several
nucleotides
with
modification of
the reading
frame)[30]
while
the others
introduce
point
mutations
R384C
[29](corresponding exactly to a
THRA mutation in a patient with
RTHa
[19])
L400R
[31]
and P398H
[32] These models
providephenotypic data that are complementary to those reported inhuman cases The growth retardation with impairment in ossi-fication is consistent in all animals [132931ndash34] The role ofTRa1
in
the development
of
chondrocytes
is probably a
deter-mining factor
as
the
elective introduction
of
the
L400R
muta-tion in the chondrocytes is sufficient to induce the phenotype[35]
The severity
of
the bone phenotype however
is
variabledepending on the models The bone phenotype of the R384Cmutation for instance was observed in young mice and dis-appeared in
the adultmice
[29]
In humans this
mutationwasreported in
a
girl though
it
is
only
known that
she
was
a
carrierof a familial form of autism without other information on herphenotype It is interesting to observe that the R384C mice hadsignificant psychomotor
disorders
with
anxiety memoryimpairment and depression (which are possible even fre-quent manifestations of autism) [3637] Cerebellar ataxiawas
also
observed
in
another
model
[31]
which
is
somewhatsimilar to the clumsiness and awkwardness described in thegait or the handling of objects in several patients with RTHa[141617] In animals these psychoneuromotor disorders arerelated
to impairment
of
neurogenesis
in
the hippocampus(lack of certain GABAergic interneurons) [38] and diminishpartially with levothyroxine [3638] This reduction on treat-ment
is not
observed
for the
bone
phenotype [39] as
was
also
reported in
humans Another
common
point of
the animalmodels
with
TRa1 mutations
is the
near-normality
of
TH
serumlevels On the other hand TSH has been found to be high inseveral
models
[1332]
as
opposed to its usual observed nor-mality in patients with RTHa (high-normal values in one case[16]) The T4T3 ratio and the reverse T3 (rT3) found to be lowin
patients with
RTHa
are
considered
an
indication of
theperipheral metabolism of TH Interestingly high levels of type1
deiodinase
(responsible for the conversion
of
T4
into
T3 andfor the clearance of rT3)have been measured in the liver of one
of the murine models [13] Normal levels were however
detected
in
another [31]Investigations of murine models found bradycardia [293132]which
was
rather
mild
but
accompanied
by
inadaptation
tostress [40] Bradycardia was reported in patients with RTHa
[141617] but the rare functional heart explorations that weredone did not demonstrate serious abnormalities [16] Bradycar-dia
is
probably
the
result
of
the
direct
effect
of
TH
on
themyocardium
(known
target
tissue
of
TH
expressing
ratherTRa1) abnormalities of calcium flux and contractility wereobserved
in
one
model
[41] However
there
is
probably
anothermechanism involved namely deregulation of the autonomicnervous
system
due
to
abnormal
brain
development
[4042]The same mechanism (lack of cerebral control on the autonomicnervous
system)
has
been
suggested
as
an
explanation
forthermogenesis
abnormalities
These
abnormalities
have
notbeen actually reported (not explored) in patients with RTHa
A
reduction
in
body
temperature
andor
a
cold
intolerance
wasdescribed in two murine models [3132] Dysfunction of thebrown fat is suspected related to deregulation of the autonomicnervous system caused by abnormal brain development [38]Increased
vasodilatation
again
related
to
the
autonomic
ner-vous
system
was
supposedly
also
observed
in
one
of
the
mo-dels with abnormal thermogenesis [43]One
patient
with
RTHa
had
weight
loss
(occurring
in
childhoodand continuing in adulthood) [21] while the other patients hadnormal or increased weight [15ndash18] One murine model exhib-ited
overweight
(without
increased
food
intake)
hepatic
stea-tosis
and
insulin
resistance
[32] but
a
controversy
exists
aboutthe real responsibility of THRA mutation Two others models hadhyperphagia without weight gain resistance to tube-feedingmild
adiposity
due
to
impairment
of
adipogenesis
and
low
liverconcentrations of lipids [44ndash46] The same mechanism aninteraction with PPARg has been suggested in both of thesecontrary
situations
[4547]
ConclusionsTowards the end of the 1980s the first descriptions of abnor-malities of the
THRB gene in patients with RTHb generated a
very
large
number
of
questions
about
the
possibility
of
muta-tions
in
the
THRA
gene
Answers
have
arrived
more
than
20
yearslater with the description of clinical phenotypes that are quite
particular
abnormalities
suggestive
of
mild
untreated
congeni-tal hypothyroidism in conjunction with thyroid function teststhat are more or less normal and therefore discordant For themoment
suggestive
symptoms
are
short
stature
hypothyroid-ism-like
facial
shape
and
low
T4T3
ratio
It
is
worthy
to
notethat
the
whole
exome
database
(httpexacbroadinstituteorg) contains 68
THRA missense or frameshift mutations with
most
of
them
predicted
to
alter
TRa1 function
It
is
thereforelikely that several patients in the general population haveundiagnosed RTHa with milder phenotype As in RTHb it is
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the discordance between the clinical and the laboratory datathat
should
stand
out
for
the
clinician
The
identification
ofpatients with authenticated abnormalities of the
THRA gene
is
essential
for
improving
the
definition
of
the
clinical
spectrumof RTHa and more generally of all RTH and syndromes of
reduced sensitivity to thyroid hormones This improved pheno-typic definition will enable genotypendashphenotype correlations tobe
formulated
and
perhaps
the
development
of
therapeuticguidelines
The
reported
cases
show
that
the
administrationof TH in patients with RTHa does not improve all the symptomsprobably
because
the
therapeutic
management
occurs
too
latefor certain abnormalities that have already become definitivelyestablished
andor
because
the
tissue
resistance
is
too
severeThe extreme dependence for TH during the brain development isa
clear
example
of
the
need
for
early
treatment
The
significance
of this seems to depend partially on the nature of the underlyinggenetic
abnormality
The
different
murine
models
with
diversegenetic abnormalities may thus be valuable tools for testing thetherapeutic
approaches
Assuming
that
the
resistance
is
toosevere to be managed by hormonal treatment identification
of the major role in animals of the interaction of mutated TRa1with corepressors such as NCoR [48] was crucial Indeed it ledto
the
demonstration
of
the
partial
reversal
of
the
abnormalTHRA
gene
phenotype
through
the
coexpression
of
a
mutantNCoR unable to interact with the TRs [49] and through theadministration
of
an
inhibitor
of
the
corepressors-associatedhistone deacetylase activity [50]
Disclosure of interest the authors declare that they have no conflicts ofinterest concerning this article
References[1] Dumitrescu AM Refetoff S The syndromes
of reduced sensitivity to thyroid hormoneBiochim Biophys Acta 201318303987ndash 4003
[2] Refetoff S DeWind LT
DeGroot LJ Familialsyndrome combining deaf-mutism stuppledepiphyses goiter and abnormally high PBIpossible target organ refractoriness to thyroidhormone J Clin Endocrinol Metab196727279ndash 94
[3] Sakurai A TakedaK Ain K Ceccarelli P NakaiA Seino S et al Generalized resistance tothyroid hormone associated with a mutationin the ligand-binding domain of the humanthyroid hormone receptor beta Proc Nat l
Acad Sci U S A 1989868977ndash 81
[4] Vlaeminck-Guillem V Margotat A Torresani J DHerbomez M Decoulx M Wemeau JLResistance to thyroid hormone in a familywith no TRbeta gene anomaly pathogenichypotheses Ann Endocrinol (Paris)200061149ndash 94
[5] Weiss RE
Hayashi Y
Nagaya T
Petty KJMurata Y Tunca H et al Dominant inheri-tance of resistance to thyroid hormone notlinked to defects in the thyroid hormonereceptor alpha or beta genes may be dueto a defective cofactor J Clin EndocrinolMetab1996814196ndash 203
[6] Pohlenz J Weiss RE
Macchia PE Pannain SLau IT Ho H et al Five new families with
resistance to thyroid hormone not caused bymutations in the thyroid hormone receptorbeta gene J Clin Endocrinol Metab1999843919ndash 28
[7] DumitrescuAM Liao XH Abdullah MS Lado-Abeal J Majed FA Moeller LC et al Muta-tions in SECISBP2 result in abnormal thyroidhormone metabolism Nat Genet2005371247ndash 52
[8] Dumitrescu AM Liao XH Best TB Brock-mann K Refetoff S A novel syndromecombining thyroid and neurological
abnormalities is associated with mutationsin a monocarboxylate transporter gene Am J Hum Genet 200474168ndash 75
[9] Friesema EC Grueters A
Biebermann HKrude H von Moers A Reeser M et alAssociation between mutations in a thyroidhormone transporter and
severe X-linked psy-chomotor retardation Lancet 20043641435ndash 7
[10] Refetoff S Bassett JH
Beck-Peccoz P Bernal JBrent G Chatterjee K et al Classificationandproposednomenclaturefor inheriteddefects ofthyroid hormone action cell transport andmetabolism Eur Thyroid J 201437ndash 9
[11] Vlaeminck-Guillem V Wemeau JL
Physiolo-gie et physiopathologie des reacutecepteurs thyr-oiumldiens lapport des modegraveles murins AnnEndocrinol (Paris) 200061440ndash 51
[12] Wikstrom L Johansson C Salto C Barlow CCampos Barros A Baas F et al Abnormalheart rate and body temperature in micelacking thyroid hormone receptor alpha 1EMBO J 199817455ndash 61
[13] Kaneshige M Suzuki H Kaneshige K Cheng J Wimbrow H Barlow C et al A targeteddominant negative mutation of the thyroidhormone alpha 1 receptor causes increasedmortality infertility and dwarfism in miceProc Natl Acad Sci U S A 20019815095ndash 100
[14] Bochukova E Schoenmakers N Agostini M
Schoenmakers E RajanayagamO Keogh JMet al A mutation in the thyroid hormonereceptor alpha gene N Engl J Med2012366243ndash 9
[15] van Mullem A van Heerebeek R Chrysis DVisser E Medici M Andrikoula M et alClinical phenotype and mutant TRalpha1 NEngl J Med 20123661451ndash 3
[16] Moran C
Schoenmakers N Agostini MSchoenmakers E Offiah A
Kydd
A et alAn adult female with resistance to thyroidhormone mediated by defective thyroid
hormone receptor alpha J Cl in EndocrinolMetab 2013984254ndash 61
[17] Moran C Agostini M Visser WE Schoen-makers E SchoenmakersN Offiah AC etalResistance to thyroid hormone caused by amutation in thyroid hormone receptor (TR)alpha1 and
TRalpha2 clinical biochemicaland genetic analyses
of three
related patientsLancet Diabet Endocrinol 20142619ndash 26
[18] van Mullem AA Chrysis D Eythimiadou AChroni E Tsatsoulis A de Rijke YB et alClinical phenotype of a new type of thyroidhormone resistance caused by a mutation ofthe TRalpha1 receptor consequences of LT4
treatment J Clin Endocrinol Metab2013983029ndash 38
[19] Yuen RK Thiruvahindrapuram B Merico DWalker S Tammimies K Hoang N et alWhole-genome sequencing of quartetfamilies with autism spectrum disorder NatMed 201521185ndash 91
[20] Tylki-Szymanska A Acuna-Hidalgo R Kra- jewska-Walasek M Lecka-Ambroziak ASteehouwer M Gi lissen C et al Thyroidhormone resistance syndrome due to muta-tions in the thyroid hormone receptor alphagene (THRA) J Med Genet 201552312ndash 6
[21] Espiard S Savagner F
Flamant F
Vlaeminck-Guillem V Guyot R Munier M
et al A novelmutation in THRA gene associated with an
atypical phenotype of resistance to thyroidhormone J Clin Endocrinol Metab 2015 jc20151120
[22] Faivre L Cormier-Daire V GenevieveD PintoG Goulet O
Munnich A
et al A novelsyndrome with dwarfism poorly muscledbuild absent clavicles humeroradial fusionslender bones oligodactyly and micro-gnathia Clin Dysmorphol 200110181ndash 4
[23] Mundlos S Cleidocranial dysplasia clinicaland molecular genetics J Med Genet199936177ndash 82
TRa receptor mutations extend the spectrum of syndromes of reduced sensitivity tothyroid hormone ENDOCRINOLOGIE
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[24] Mundlos S Otto F
Mundlos C Mulliken JBAylsworth AS Albright S et a l Mutat ionsinvolving the transcription factor CBFA1
causecleidocranial dysplasia Cell 199789773ndash 9
[25] Margotat A
Sarkissian G Malezet-Desmou-lins C Peyrol N Vlaeminck Guillem V
Wemeau JL
et al Ident if ication of eightnew mutations in the c-erbAB gene ofpatients with resistance to thyroid hormoneAnn Endocrinol 200162220ndash 5
[26] Adams M Matthews C Coll ingwood TNToneY
Beck-Peccoz P ChatterjeeKK Geneticanalysis of 29 kindreds with generalized andpituitary resistance to thyroid hormone Iden-tification of thirteen novel mutations in thethyroid hormone receptor beta gene J ClinInvest 199494506ndash 15
[27] Groenhout EG Dorin RI Generalized thyroidhormone resistance due to a deletion of thecarboxy terminus of the c-erbA beta receptorMol Cell Endocrinol 19949981ndash 8
[28] Wu SY CohenRN SimsekE Senses DA Yar
NE Grasberger H et al A novel thyroidhormone receptor-beta mutation that failsto bind nuclear receptor corepressor in apatient as an apparent cause of severe pre-dominantly pituitary resistance to thyroid hor-mone J Clin Endocrinol Metab 2006911887ndash 95
[29] Tinnikov A Nordstrom K Thoren P Kindblom JM Malin S Rozell B et al Retardation ofpost-natal development caused by a nega-tively acting thyroid hormone receptoralpha1 EMBO J 2002215079ndash 87
[30] Parrilla R
Mixson AJ McPherson JA
McClas-key JH Weintraub BD Characterization ofseven novel mutations of the c-erbA betagene in unrelated kindreds with generalizedthyroidhormone resistance Evidence for twohot spot regions of the l igand bindingdomain J Clin Invest 1991882123ndash 30
[31] Quignodon L VincentS Winter H Samarut JFlamant F A point mutation in the
activationfunction2 domainof thyroidhormonereceptoralpha1 expressed after CRE-mediated recom-bination partially recapitulates hypothyroid-ism Mol Endocrinol 2007212350ndash 60
[32] Liu YY
Schultz JJ
Brent GA A thyroidhormone receptor alpha gene mutation
(P398H) is associated with visceral adiposityand impaired catecholamine-stimulated lipo-lysis in mice J Biol Chem 200327838913ndash 20
[33] OShea PJ Bassett JH ChengSY Williams GRCharacterization of skeletal phenotypes ofTRalpha1 and TRbeta mutant mice implica-
tions for tissue thyroid status and T3 targetgene expression Nucl Recept Signal 20064e011
[34] OShea PJ Bassett JH Sriskantharajah S YingH Cheng SY Williams GR Contrasting ske-leta l phenotypes in mice with an identicalmutation targeted to thyroid hormone recep-tor alpha1 or beta Mol Endocrinol2005193045ndash 59
[35] Desjardin C
Charles C
Benoist-Lasselin CRiviere J Gilles M Chassande O et alChondrocytes play a major role in the stimu-lation of bone growth by thyroid hormoneEndocrinology 20141553123ndash 35
[36] Venero C Guadano-Ferraz A Herrero AINordstrom K Manzano J de Escobar GM
et al Anxiety memory impairmentand loco-motor dysfunction caused by a mutant thyr-oid hormone receptor alpha1 can beameliorated by T3 treatment Genes Dev2005192152ndash 63
[37] Pilhatsch M
Winter C
Nordstrom K Venn-strom B Bauer M
Juckel G Increaseddepressive behaviour in mice harboring themutant thyroid hormone receptor alpha 1Behav Brain Res 2010214187ndash 92
[38] Kapoor R
van Hogerlinden M
Wallis KGhosh H Nordstrom K Vennstrom Bet al Unliganded thyroid hormone receptoralpha1 impairs adult hippocampal neurogen-esis FASEB J 2010244793ndash 805
[39] Bassett JH Boyde A Zikmund T Evans HCroucher PI
Zhu X
et al
Thyroid hormonereceptor alpha mutation causes a severe
andthyroxine-resistant skeletaldysplasiain femalemice Endocrinology 20141553699ndash 712
[40] Mittag J Davis B Vujovic M Arner AVennstromB Adaptations of theautonomousnervous system controlling heart rate areimpairedby amutant thyroid hormone recep-tor-alpha1 Endocrinology 20101512388ndash 95
[41] Tavi P Sjogren M Lunde PK Zhang SJAbbate F
Vennstrom B et al Impaired
Ca2+ handling and contraction in cardiomyo-cytes from mice with a dominant negativethyroid hormone receptor alpha1 J Mol CellCardiol 200538655ndash 63
[42] Mittag J Lyons DJ Sall strom J Vujovic MDudazy-Gralla S Warner A
et al Thyroid
hormone is required for hypothalamic neu-rons regulating cardiovascular functions J ClinInvest 2013123509ndash 16
[43] Warner A RahmanA Solsjo P Gottschling KDavis B Vennstrom B et al Inappropriateheatdissipation ignitesbrown fat thermogen-esis in mice with a mutant thyroid hormonereceptor alpha1 Proc Natl Acad Sci U S A201311016241ndash 46
[44] SjogrenM AlkemadeA
MittagJ
NordstromK KatzA Rozell B etal Hypermetabolisminmice caused by the central action of an unli-ganded thyroid hormone receptor alpha1EMBO J 2007264535ndash 45
[45] Ying H Araki O Furuya F Kato Y Cheng SYImpaired adipogenesis caused by a mutated
thyroid hormone alpha1 receptor Mol CellBiol 2007272359ndash 71
[46] Araki O
Ying H Zhu XG Willingham MCChengSY Distinct dysregulationof lipid meta-bolismbyunligandedthyroid hormone recep-tor isoforms Mol Endocrinol 200923308ndash 15
[47] Liu YY
Heymann RS Moatamed F
Schultz JJSobel D Brent GA A mutant thyroid hor-mone receptor alphaantagonizesperoxisomeproliferator-activated receptor alpha signalingin vivo and impairs fatty acid oxidation Endo-crinology 20071481206ndash 17
[48] Fozzatt i L Lu C
Kim DW Cheng SY Differ-ential recruitment of nuclear coregulatorsdirects the isoform-dependent action ofmutant thyroid hormonereceptorsMol Endo-crinol 201125908
ndash 21
[49] Fozzatti
L Kim
DW
ParkJW Willingham
MCHollenberg AN Cheng SY Nuclear receptorcorepresso r (NCOR1) regulates in vivoactions ofa mutated
thyroid
hormone recep-tor alpha Proc Natl
Acad
Sci U S A20131107850ndash 5
[50] Kim DW ParkJW
Willingham MC Cheng SYA histone deacetylase inhibitor improveshypothyroidism caused by a TRalpha1mutant Hum Mol Genet 2014232651ndash 64
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coordination learning to walk and reading Mild to severeintellectual
deficit
has
often
been
reported
but
is
not
systematic[2021] Constipation is nearly constant with an early appear-ance
in
childhood
one
case
of
diarrhoea
occurring
late
inadulthood was described [21] Bradycardia another sign sug-
gestive of hypothyroidism is sometimes reported [141617]Overweight is also possible particularly in adults [15ndash18] Bodytemperature
appears
normal
[1518] whereas
the
baselinemetabolism
is
decreased
[14161721] Finally
cases
of
carpaltunnel syndrome have been reported [17] as is sometimesdescribed
in
association
with
myxoedema
of
hypothyroidismThe routine laboratory tests are normal except for anaemiawhich
is
consistently
present
in
all
clinical
descriptions
but
israther moderate It is usually normocytic though sometimesmacrocytic
[1721]) Hypercholesterolemia
may
also
occur[15ndash1820] Insulin-like
growth
factor
1
may
be
low
in
childrenand adolescents patients [14ndash1618]
Radiological
exams
are
done
to
investigate
potential
malforma-tion syndromes [2021] Skull X-rays in children confirm macro-cephaly and show delay of ossification in the fontanels and thepersistence of wormian bones (which reflect ossification abnor-malities)
[14]
Ossification
delay
is
also
evidenced
by
epiphysealdysgenesis
(femoral
heads)
[141518]
and
by
delayed
boneage An ovoid appearance of the vertebrae is possible [20] Inadults
X-rays
again
show
macrocephaly
with
thickening
of
theskull vault (occipital in particular) and enlargement of the frontalbone [1617] Cortical bone thickening has also been describedon
the
long
bones
of
the
limbs
[16] Osteodensitometric
meas-urements
in
adults
are
usually
normal
[16ndash1821]The signs of hypothyroidism that are typically found lead logi-cally to an investigation of thyroid function tests Though pro-viding
reassurance
when
values
are
normal
or
low
normal
they
must attract attention when there is a discrepancy with the
clinical
presentation
It
is
this
dissociation
between
normallaboratory values and the more or less pronounced signs ofhypothyroidism
(including
the
dysmorphic
syndrome)
thatshould suggest the diagnosis of RTHa It is the opposite condi-
tion of RTHb where the symptoms of hyperthyroidism are ratherminimal in association with laboratory indications of hyperthy-roidism
(table
II )
In
this
respect
it
can
be
seen
that
thedissociation
between
the
clinical
and
laboratory
observationsis a key element of RTH both in the alpha and the beta formsThe
thyroid
hormone
values
both
in
their
free
and
total
formsare more or less normal There is a tendency however for T4 tobe
slightly
low
and
T3
slightly
high
As
a
result
there
is
adecreased T4T3 ratio which was the only consistent factorin
all
the
published
cases
The
TSH
is
normal
(though
low
insome
cases)
It
should
be
noted
that
neonatal
screening
forhypothyroidism which is based on TSH cannot identify RTHa
Several
patients
received
treatment
with
levothyroxine
some-times even before the clinical or specific molecular diagnosisThe clinical effects are inconclusive particularly because cogni-tive disorders and dysmorphic syndrome are often alreadyestablished
and
definitive
[14] Benefits
can
be
seen
for
brady-cardia
energy
levels
bowel
function
and
carpal
tunnel
syn-drome [1617] There is usually an increase in the concentrationsof
thyroid
hormones
and
a
quick
and
predictable
suppression
ofTSH which reflects the successful adaptation of the hypotha-lamic-pituitary axis Improvement of the other abnormal labo-ratory
values
(blood
cholesterol
anaemia)
is
not
constant
Molecular bases of RTHa
The functional thyroid receptors are the isoforms TRb1 TRb2andTRa1 They are present in the nucleus of the target cells as
TABLE IIClinical
and
biological
phenotypes
of
the
a
and
b
syndromes
of
resistance
to
thyroid
hormones
RTHa RTHb
Involved gene THRA THRB
Involved receptors TRa11 TRb1TRb2
Clinical phenotype Mild hypothyroidism(short height dysmorphic syndrom)
Mild hyperthyroidism (tachycardia nervousness)
Goiter No Yes
fT3 High-normal High
fT4 Low normal High
T4T3 ratio Low Low
TSH Normal or low High
1Some mutations of the THRA gene also involve non-functional isoforms such as the TRa2 protein
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dimers They are capable of binding on theDNA specific targetsequences (thyroid
hormone response elements
or
TREs)which are located in the regulatory sequences (promotersenhancers) of
the target
genes Like the other
nuclear
recep-tors they in fact behave like ligand-inducible transcription
factors In the absence of hormones and through interactionwith cofactors that repress their transcriptional activity (core-pressors) the
TR reduces
the expression
of
the target
genesLigandbindingenables the TR to releasecorepressors to
recruitactivating partners of transcription (coactivators) and to theninduce
the transcription
of
the target
genes
To
fulfil all
thesefunctions (DNA-binding hormone binding transactivationactivity) the TRs are
organized
into
modules an
N -terminustransactivation domain a DNA-binding domain (DBD) a hingedomain
and a
ligand-binding domain
(LBD) Organized
as
asuccession
of
12
helices this last domain
has on
its C -terminusthe transactivation domain the activity of which is exerted in
the presence
of
the ligand
Indeedmodifications
of
the recep-tor structure occur during hormone binding and involve moreparticularly the 12th helix (H12) which includes the last C -terminus amino acidsIn
the
b
form
of
RTH
the
abnormality
is
carried
by
the
THRB
gene
The
mutations
are
essentially
distributed
over
the
LBD
andthe hinge domain (they do not affect the DNA-binding domainor
the
N -terminus
transactivation
domain)
(1047297 gure
1)
Threeregions rich in cytosine and guanine clusters (CpG islands)are particularly subject to genetic abnormalities (hot spots)[1]
even
though
some
mutations
have
been
reported
outsideof
these
hot
spots
[25] The
two functional
isoforms
producedfrom the THRB gene differing at their N -terminus (TRb1 andTRb2) are both concerned by these
C -terminus abnormalitiesDNA
binding
is
preserved
and
classically
the
mutated
receptorshave a reduced or absence of affinity for T3 They can also havenormal affinity for T3 but a constitutional inability to interactwith
coactivators
[1]
The
phenotype
is
expressed
while
a
singlecopy of the gene is usually involved (heterozygous mutation)The explanation lies in a dominant negative activity exerted bythe mutant receptors on the still functional isoforms By dime-rizing
with
them
they
prevent
the
release
of
the
corepressorsthe recruitment of the coactivators and finally transcriptionalactivity In 90 of cases the identified mutations are missensepoint
mutations
(a
nucleotide
base
is
changed
into
another
resulting
in
an
amino
acid
substitution
on
the
protein
[1])Sometimes
the
point
mutation
is
a
nonsense
mutation
(whichstops protein translation) it may involve the deletion or inser-tion
of
a
nucleotide
base
which
then
leads
to
a
modification
ofthe reading frame and translation of the genetic message intoan erroneous protein message In the case of nonsense muta-tions
or
modifications
of
the
reading
frame
the
affected
recep-tors are truncated on a more or less long part of their
C -terminusCurrently
close
to
500
families
have
thus
been
identified
ascarriers of a THRB gene abnormality and close to 200 different
mutations have been identified (the same mutation may becarried by several different families) [1]As
of
now
there
are
8
known
different
mutations
affecting
theTHRA gene in patients with RTHa (table III ) As with THRB theyare located in the ligand-binding domain (1047297 gure
2) They alsoinvolve
point
mutations
(missense
or
nonsense)
or
abnormali-ties (insertion or deletion of a nucleotide) that result in modifi-cation of the reading frame thus causing a truncated receptorAs with RTHb point mutations seem to be predominant (6 out of8
times)
These
were
de
novo
mutations
in
6
patients
In4 patients the abnormality occurred through autosomal domi-nant transmission by an affected parent (father or mother)Contrary
to
isoforms
TRb1 and
TRb2
which
differ
on
their
N -
terminus
the
main
isoforms
produced
from
the
THRA
geneTRa1
and
TRa2
differ
on
their
C -terminus
They
share
a
commonprotein sequence up until the 360th amino acid the sequencesthen
diverge
resulting
in
a
functional
LBD
for
TRa1
and
an
LBDthat is incapable of binding T3 for TRa2 Six of the eight abnor-malities detected are located in the part of the gene concerningonly
TRa1 [14ndash161920] the
two
others
concern
the
commonsequence between TRa1 and TRa2 [1721] Several of themutations
identified
in
the
THRA
gene
in
cases
of
RTHa
werealso identified in the THRB gene in cases of RTHb A263V (THRA)
Figure
1
The
main
isoforms
produced
by
the
THRB
gene
and
themutations
described
in
the
b
form
of
resistance
to
thyroid
hormonesThe isoforms TRb1 and TRb2 are functional receptors capable of binding DNA and T3
and
influencing under the control of the latter the expression of target genes The
mutations found in RTHb are concentrated in the T3 binding domain (E)and thehinge
domain (D) which separates it from the DNA-binding domain (C) and theN -terminus
transactivation domain (AB) Theyare present in the common sequenceof isoforms
TRb1
and TRb2 Three areas are particularly sensitive to mutations (hot spots) and
are foundbetween aminoacids234and 282 ( 1) 309 and 353 ( 2) and 426 and
460 ( 3 numbering in 461 amino acids of the TRb1
receptor)
TRa
receptor mutations extend the spectrum of syndromes of reduced sensitivity tothyroid hormone ENDOCRINOLOGIE
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and
A317V
(THRB) [17] R384C
and
R438C
[1926] C392X
andC446X
mutations
[2027] Modification
of
the
reading
framefrom amino acid 382 in TRa1 (due to the insertion of a nucleo-tide base in the
THRA gene) [15] has also been reported in the
equivalent
residue
of
TRb1TRb2 (insertions
of
several
bases
inthe THRB gene) [28] although the erroneous consecutivesequence is not the same For the other
THRA gene mutations
with
no
strict
equivalent
in
the
THRB
gene
similar
mutationshave been described either resulting in another substitution oroccurring in a neighbouring residue One notable exceptionhowever is the N359Y mutation [21] which has no strictequivalent
and
in
which
the
corresponding
amino
acid
in
theTRb1TRb2 sequence is not in one of the three known hotspots (a partial explanation for this may lie in the distinctivefeatures
of
the
phenotype
associated
with
this
mutation
see
below)
In
any
case
comparison
of
the a
and b
forms
of
RTH
foridentical
or
equivalent
mutations
enables
the
respective
rolesof the different receptors to be specified In general then the b
receptors
seem
to
be
clearly
involved
in
the
hypothalamic-pituitary feedback loop while the a receptors are more involvedin the peripheral effects of THSeveral
TRa1 mutants
have
been
examined
in
functional
stud-ies Their common points include their incapability to induce theexpression
of
target
genes
and
their
dominant
negative
repres-sor activity over the normal TRa1 receptor [14ndash172129] When
it
was
evaluated
the
affinity
for
T3
was
reduced
[161721]Moreover
the
dominant
negative
activity
seems
to
be
exertedon the TRb1 receptor [152129] The still small number ofreported cases does not enable the formulation of genotypendashphenotype
correlations
For
example
only
two
mutations
affectboth TRa1 and TRa2 While the A263V mutation does not resultin a phenotype different from that observed for mutations thatonly
affect
TRa1 [17]the
phenotype
associated
with
the
N359Ymutation is particular due to the incidence (coincidental) of amarked malformation syndrome and hypercalcemia from para-thyroid hyperplasia and even to the absence of constipation andintellectual
deficit
(though
this
absence
has
also
been
observedin other cases) [21] Whether other isoforms produced from theTHRA
gene (TRa3 p43 P30 TRD1 and TRD2) are implicated inthe
phenotype
also
deserves
to
be
explored
[21] Although
this
needs
to
be
substantiated
with
subsequent
clinical
cases
thereis
a
tendency
for
more
serious
forms
to
exist
with
the
mutationoccurring early in the sequence and resulting in truncation Themost
significant
intellectual
deficit
(IQ
of
22)
was
described
forthe mutation involving the 18 amino acid deletion of TRa1 [20]Conversely patients with normal IQs are carriers of missensepoint
mutations
that
only
substitute
one
amino
acid
for
another[2021] In RTHb the severe forms are also often related toTRb1TRb2
truncations
[28] It
is
likely
that
truncations
(result-ing in the lack of C -terminal helix 12) induce more severe
TABLE IIIDescription
of
the
known
mutations
in
THRA
gene
(encoding
the
thyroid
hormone
receptor
TRa1)
in
patients
with
the a
syndrome
of
resistance
to
thyroid
hormone
Protein
mutation1
Number of
involvedfamilies
Number of
involvedpatients
THRA gene mutations2 Type of protein
mutation
Consequences for protein
functions
Involved
isoforms
References
A263V 1 3 Single base substitution (CxxxxT) Missense Single aminoacid substitution TRa1TRa2
[17]
N359Y 1 1 Single base substitution (C1075G) Missense Single aminoacid substitution TRa1TRa2
[21]
A382fs388X 1 1 Single base deletion(1144delG)
Frameshift Wrong sequence from A382then premature truncation at
position 388
TRa1 [16]
R384C 1 1 Single base substitution (C1150 T) Missense Single aminoacid substitution TRa1 [19]
C392X 1 1 Single base substitution (C1176A) No-sense Premature truncation atposition C392
TRa1 [20]
F397fs406X 1 2 Single base insertion(1144insT) Frameshift
Wrong sequence from F397then premature truncation atposition 406
TRa1 [1518]
P398R 1 1 Single base substitution (C1150 T) Missense Single aminoacid substitution TRa1 [20]
E403X 3 4 Single base substitution (C1176A) No-sense Premature truncation atposition E403
TRa1 [1420]
1The numbering is based on the TRa1 protein sequence (common to the TRa2 sequence until the amicoacid 360)2All mutations are located in exon 9 of the THRA gene (last exon of TRa1 and the secondlast for TRa2)
V Vlaeminck-Guillem S Espiard F Flamant J-LWeacutemeau
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Figure 2
The
main
isoforms
produced
by
the
THRA
gene
and
the
mutations
described
in
the
a
form
of
resistance
to
thyroid
hormonesIsoform TRa1 isa functional receptor capable of binding DNA and T3 and influencingunder thecontrolof thelatter theexpression of target genes Isoform TRa2
is incapable of
binding thehormoneand behaves like a weak dominant negative inhibitor of the T3 functionalreceptorsFor now themutations found in RTHa rein the T3 binding domain (E)
while
thehinge domain(D) theDNA-binding domain (C)and theN -terminus transactivation domain (AB) arespared Themutationsconcern the commonsequence of thetwo
isoforms TRa1andTRa2 oronlyaffectthe C -terminussequence of TRa1 (numbering in410 amino acids ofthe TRa1 receptor) Thepoint mutations arerepresentedby a star and
the
frameshift mutations by a star at the level of the first mutated amino acid fol lowed by a blue box representing the modified sequence
The four mutations introduced in the THRA gene to try to generate murine models of the a form of resistance to thyroid hormones are also indicated in italic font (R384C
P394fs406X P398H and L400R) The numbering for the murine isoform TRa1
is the same as for the human isoform
TRa receptor mutations extend the spectrum of syndromes of reduced sensitivity tothyroid hormone ENDOCRINOLOGIE
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phenotype by profoundly affecting TR function through totalinability
to
interact
with
coactivatorsThe genotypendashphenotype correlations may in fact need to beinvestigatedin
animal
modelsMicewith
complete
inactivationof the THRA andor
THRB genes have been reported [11] but
may not represent the most relevant models as the absence ofa receptor does nothave the same consequences as the expres-sion
of
an
abnormal receptor
The comparison
is
more
logical inanimal
models
with
an
artificially
introduced
mutation For theTHRA
gene thereare fourdifferentmodels available that are allbased
on
a
mutation
of
the hormone-binding domain in
onlythe TRa1 receptor (1047297 gure 2 no model with mutation affectingTRa1
and TRa2)
One model
introduced
in
TRa1 the PV
muta-tion [13] which was identified in a patientwith RTHb (insertionof
several
nucleotides
with
modification of
the reading
frame)[30]
while
the others
introduce
point
mutations
R384C
[29](corresponding exactly to a
THRA mutation in a patient with
RTHa
[19])
L400R
[31]
and P398H
[32] These models
providephenotypic data that are complementary to those reported inhuman cases The growth retardation with impairment in ossi-fication is consistent in all animals [132931ndash34] The role ofTRa1
in
the development
of
chondrocytes
is probably a
deter-mining factor
as
the
elective introduction
of
the
L400R
muta-tion in the chondrocytes is sufficient to induce the phenotype[35]
The severity
of
the bone phenotype however
is
variabledepending on the models The bone phenotype of the R384Cmutation for instance was observed in young mice and dis-appeared in
the adultmice
[29]
In humans this
mutationwasreported in
a
girl though
it
is
only
known that
she
was
a
carrierof a familial form of autism without other information on herphenotype It is interesting to observe that the R384C mice hadsignificant psychomotor
disorders
with
anxiety memoryimpairment and depression (which are possible even fre-quent manifestations of autism) [3637] Cerebellar ataxiawas
also
observed
in
another
model
[31]
which
is
somewhatsimilar to the clumsiness and awkwardness described in thegait or the handling of objects in several patients with RTHa[141617] In animals these psychoneuromotor disorders arerelated
to impairment
of
neurogenesis
in
the hippocampus(lack of certain GABAergic interneurons) [38] and diminishpartially with levothyroxine [3638] This reduction on treat-ment
is not
observed
for the
bone
phenotype [39] as
was
also
reported in
humans Another
common
point of
the animalmodels
with
TRa1 mutations
is the
near-normality
of
TH
serumlevels On the other hand TSH has been found to be high inseveral
models
[1332]
as
opposed to its usual observed nor-mality in patients with RTHa (high-normal values in one case[16]) The T4T3 ratio and the reverse T3 (rT3) found to be lowin
patients with
RTHa
are
considered
an
indication of
theperipheral metabolism of TH Interestingly high levels of type1
deiodinase
(responsible for the conversion
of
T4
into
T3 andfor the clearance of rT3)have been measured in the liver of one
of the murine models [13] Normal levels were however
detected
in
another [31]Investigations of murine models found bradycardia [293132]which
was
rather
mild
but
accompanied
by
inadaptation
tostress [40] Bradycardia was reported in patients with RTHa
[141617] but the rare functional heart explorations that weredone did not demonstrate serious abnormalities [16] Bradycar-dia
is
probably
the
result
of
the
direct
effect
of
TH
on
themyocardium
(known
target
tissue
of
TH
expressing
ratherTRa1) abnormalities of calcium flux and contractility wereobserved
in
one
model
[41] However
there
is
probably
anothermechanism involved namely deregulation of the autonomicnervous
system
due
to
abnormal
brain
development
[4042]The same mechanism (lack of cerebral control on the autonomicnervous
system)
has
been
suggested
as
an
explanation
forthermogenesis
abnormalities
These
abnormalities
have
notbeen actually reported (not explored) in patients with RTHa
A
reduction
in
body
temperature
andor
a
cold
intolerance
wasdescribed in two murine models [3132] Dysfunction of thebrown fat is suspected related to deregulation of the autonomicnervous system caused by abnormal brain development [38]Increased
vasodilatation
again
related
to
the
autonomic
ner-vous
system
was
supposedly
also
observed
in
one
of
the
mo-dels with abnormal thermogenesis [43]One
patient
with
RTHa
had
weight
loss
(occurring
in
childhoodand continuing in adulthood) [21] while the other patients hadnormal or increased weight [15ndash18] One murine model exhib-ited
overweight
(without
increased
food
intake)
hepatic
stea-tosis
and
insulin
resistance
[32] but
a
controversy
exists
aboutthe real responsibility of THRA mutation Two others models hadhyperphagia without weight gain resistance to tube-feedingmild
adiposity
due
to
impairment
of
adipogenesis
and
low
liverconcentrations of lipids [44ndash46] The same mechanism aninteraction with PPARg has been suggested in both of thesecontrary
situations
[4547]
ConclusionsTowards the end of the 1980s the first descriptions of abnor-malities of the
THRB gene in patients with RTHb generated a
very
large
number
of
questions
about
the
possibility
of
muta-tions
in
the
THRA
gene
Answers
have
arrived
more
than
20
yearslater with the description of clinical phenotypes that are quite
particular
abnormalities
suggestive
of
mild
untreated
congeni-tal hypothyroidism in conjunction with thyroid function teststhat are more or less normal and therefore discordant For themoment
suggestive
symptoms
are
short
stature
hypothyroid-ism-like
facial
shape
and
low
T4T3
ratio
It
is
worthy
to
notethat
the
whole
exome
database
(httpexacbroadinstituteorg) contains 68
THRA missense or frameshift mutations with
most
of
them
predicted
to
alter
TRa1 function
It
is
thereforelikely that several patients in the general population haveundiagnosed RTHa with milder phenotype As in RTHb it is
V Vlaeminck-Guillem S Espiard F Flamant J-LWeacutemeau
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the discordance between the clinical and the laboratory datathat
should
stand
out
for
the
clinician
The
identification
ofpatients with authenticated abnormalities of the
THRA gene
is
essential
for
improving
the
definition
of
the
clinical
spectrumof RTHa and more generally of all RTH and syndromes of
reduced sensitivity to thyroid hormones This improved pheno-typic definition will enable genotypendashphenotype correlations tobe
formulated
and
perhaps
the
development
of
therapeuticguidelines
The
reported
cases
show
that
the
administrationof TH in patients with RTHa does not improve all the symptomsprobably
because
the
therapeutic
management
occurs
too
latefor certain abnormalities that have already become definitivelyestablished
andor
because
the
tissue
resistance
is
too
severeThe extreme dependence for TH during the brain development isa
clear
example
of
the
need
for
early
treatment
The
significance
of this seems to depend partially on the nature of the underlyinggenetic
abnormality
The
different
murine
models
with
diversegenetic abnormalities may thus be valuable tools for testing thetherapeutic
approaches
Assuming
that
the
resistance
is
toosevere to be managed by hormonal treatment identification
of the major role in animals of the interaction of mutated TRa1with corepressors such as NCoR [48] was crucial Indeed it ledto
the
demonstration
of
the
partial
reversal
of
the
abnormalTHRA
gene
phenotype
through
the
coexpression
of
a
mutantNCoR unable to interact with the TRs [49] and through theadministration
of
an
inhibitor
of
the
corepressors-associatedhistone deacetylase activity [50]
Disclosure of interest the authors declare that they have no conflicts ofinterest concerning this article
References[1] Dumitrescu AM Refetoff S The syndromes
of reduced sensitivity to thyroid hormoneBiochim Biophys Acta 201318303987ndash 4003
[2] Refetoff S DeWind LT
DeGroot LJ Familialsyndrome combining deaf-mutism stuppledepiphyses goiter and abnormally high PBIpossible target organ refractoriness to thyroidhormone J Clin Endocrinol Metab196727279ndash 94
[3] Sakurai A TakedaK Ain K Ceccarelli P NakaiA Seino S et al Generalized resistance tothyroid hormone associated with a mutationin the ligand-binding domain of the humanthyroid hormone receptor beta Proc Nat l
Acad Sci U S A 1989868977ndash 81
[4] Vlaeminck-Guillem V Margotat A Torresani J DHerbomez M Decoulx M Wemeau JLResistance to thyroid hormone in a familywith no TRbeta gene anomaly pathogenichypotheses Ann Endocrinol (Paris)200061149ndash 94
[5] Weiss RE
Hayashi Y
Nagaya T
Petty KJMurata Y Tunca H et al Dominant inheri-tance of resistance to thyroid hormone notlinked to defects in the thyroid hormonereceptor alpha or beta genes may be dueto a defective cofactor J Clin EndocrinolMetab1996814196ndash 203
[6] Pohlenz J Weiss RE
Macchia PE Pannain SLau IT Ho H et al Five new families with
resistance to thyroid hormone not caused bymutations in the thyroid hormone receptorbeta gene J Clin Endocrinol Metab1999843919ndash 28
[7] DumitrescuAM Liao XH Abdullah MS Lado-Abeal J Majed FA Moeller LC et al Muta-tions in SECISBP2 result in abnormal thyroidhormone metabolism Nat Genet2005371247ndash 52
[8] Dumitrescu AM Liao XH Best TB Brock-mann K Refetoff S A novel syndromecombining thyroid and neurological
abnormalities is associated with mutationsin a monocarboxylate transporter gene Am J Hum Genet 200474168ndash 75
[9] Friesema EC Grueters A
Biebermann HKrude H von Moers A Reeser M et alAssociation between mutations in a thyroidhormone transporter and
severe X-linked psy-chomotor retardation Lancet 20043641435ndash 7
[10] Refetoff S Bassett JH
Beck-Peccoz P Bernal JBrent G Chatterjee K et al Classificationandproposednomenclaturefor inheriteddefects ofthyroid hormone action cell transport andmetabolism Eur Thyroid J 201437ndash 9
[11] Vlaeminck-Guillem V Wemeau JL
Physiolo-gie et physiopathologie des reacutecepteurs thyr-oiumldiens lapport des modegraveles murins AnnEndocrinol (Paris) 200061440ndash 51
[12] Wikstrom L Johansson C Salto C Barlow CCampos Barros A Baas F et al Abnormalheart rate and body temperature in micelacking thyroid hormone receptor alpha 1EMBO J 199817455ndash 61
[13] Kaneshige M Suzuki H Kaneshige K Cheng J Wimbrow H Barlow C et al A targeteddominant negative mutation of the thyroidhormone alpha 1 receptor causes increasedmortality infertility and dwarfism in miceProc Natl Acad Sci U S A 20019815095ndash 100
[14] Bochukova E Schoenmakers N Agostini M
Schoenmakers E RajanayagamO Keogh JMet al A mutation in the thyroid hormonereceptor alpha gene N Engl J Med2012366243ndash 9
[15] van Mullem A van Heerebeek R Chrysis DVisser E Medici M Andrikoula M et alClinical phenotype and mutant TRalpha1 NEngl J Med 20123661451ndash 3
[16] Moran C
Schoenmakers N Agostini MSchoenmakers E Offiah A
Kydd
A et alAn adult female with resistance to thyroidhormone mediated by defective thyroid
hormone receptor alpha J Cl in EndocrinolMetab 2013984254ndash 61
[17] Moran C Agostini M Visser WE Schoen-makers E SchoenmakersN Offiah AC etalResistance to thyroid hormone caused by amutation in thyroid hormone receptor (TR)alpha1 and
TRalpha2 clinical biochemicaland genetic analyses
of three
related patientsLancet Diabet Endocrinol 20142619ndash 26
[18] van Mullem AA Chrysis D Eythimiadou AChroni E Tsatsoulis A de Rijke YB et alClinical phenotype of a new type of thyroidhormone resistance caused by a mutation ofthe TRalpha1 receptor consequences of LT4
treatment J Clin Endocrinol Metab2013983029ndash 38
[19] Yuen RK Thiruvahindrapuram B Merico DWalker S Tammimies K Hoang N et alWhole-genome sequencing of quartetfamilies with autism spectrum disorder NatMed 201521185ndash 91
[20] Tylki-Szymanska A Acuna-Hidalgo R Kra- jewska-Walasek M Lecka-Ambroziak ASteehouwer M Gi lissen C et al Thyroidhormone resistance syndrome due to muta-tions in the thyroid hormone receptor alphagene (THRA) J Med Genet 201552312ndash 6
[21] Espiard S Savagner F
Flamant F
Vlaeminck-Guillem V Guyot R Munier M
et al A novelmutation in THRA gene associated with an
atypical phenotype of resistance to thyroidhormone J Clin Endocrinol Metab 2015 jc20151120
[22] Faivre L Cormier-Daire V GenevieveD PintoG Goulet O
Munnich A
et al A novelsyndrome with dwarfism poorly muscledbuild absent clavicles humeroradial fusionslender bones oligodactyly and micro-gnathia Clin Dysmorphol 200110181ndash 4
[23] Mundlos S Cleidocranial dysplasia clinicaland molecular genetics J Med Genet199936177ndash 82
TRa receptor mutations extend the spectrum of syndromes of reduced sensitivity tothyroid hormone ENDOCRINOLOGIE
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[24] Mundlos S Otto F
Mundlos C Mulliken JBAylsworth AS Albright S et a l Mutat ionsinvolving the transcription factor CBFA1
causecleidocranial dysplasia Cell 199789773ndash 9
[25] Margotat A
Sarkissian G Malezet-Desmou-lins C Peyrol N Vlaeminck Guillem V
Wemeau JL
et al Ident if ication of eightnew mutations in the c-erbAB gene ofpatients with resistance to thyroid hormoneAnn Endocrinol 200162220ndash 5
[26] Adams M Matthews C Coll ingwood TNToneY
Beck-Peccoz P ChatterjeeKK Geneticanalysis of 29 kindreds with generalized andpituitary resistance to thyroid hormone Iden-tification of thirteen novel mutations in thethyroid hormone receptor beta gene J ClinInvest 199494506ndash 15
[27] Groenhout EG Dorin RI Generalized thyroidhormone resistance due to a deletion of thecarboxy terminus of the c-erbA beta receptorMol Cell Endocrinol 19949981ndash 8
[28] Wu SY CohenRN SimsekE Senses DA Yar
NE Grasberger H et al A novel thyroidhormone receptor-beta mutation that failsto bind nuclear receptor corepressor in apatient as an apparent cause of severe pre-dominantly pituitary resistance to thyroid hor-mone J Clin Endocrinol Metab 2006911887ndash 95
[29] Tinnikov A Nordstrom K Thoren P Kindblom JM Malin S Rozell B et al Retardation ofpost-natal development caused by a nega-tively acting thyroid hormone receptoralpha1 EMBO J 2002215079ndash 87
[30] Parrilla R
Mixson AJ McPherson JA
McClas-key JH Weintraub BD Characterization ofseven novel mutations of the c-erbA betagene in unrelated kindreds with generalizedthyroidhormone resistance Evidence for twohot spot regions of the l igand bindingdomain J Clin Invest 1991882123ndash 30
[31] Quignodon L VincentS Winter H Samarut JFlamant F A point mutation in the
activationfunction2 domainof thyroidhormonereceptoralpha1 expressed after CRE-mediated recom-bination partially recapitulates hypothyroid-ism Mol Endocrinol 2007212350ndash 60
[32] Liu YY
Schultz JJ
Brent GA A thyroidhormone receptor alpha gene mutation
(P398H) is associated with visceral adiposityand impaired catecholamine-stimulated lipo-lysis in mice J Biol Chem 200327838913ndash 20
[33] OShea PJ Bassett JH ChengSY Williams GRCharacterization of skeletal phenotypes ofTRalpha1 and TRbeta mutant mice implica-
tions for tissue thyroid status and T3 targetgene expression Nucl Recept Signal 20064e011
[34] OShea PJ Bassett JH Sriskantharajah S YingH Cheng SY Williams GR Contrasting ske-leta l phenotypes in mice with an identicalmutation targeted to thyroid hormone recep-tor alpha1 or beta Mol Endocrinol2005193045ndash 59
[35] Desjardin C
Charles C
Benoist-Lasselin CRiviere J Gilles M Chassande O et alChondrocytes play a major role in the stimu-lation of bone growth by thyroid hormoneEndocrinology 20141553123ndash 35
[36] Venero C Guadano-Ferraz A Herrero AINordstrom K Manzano J de Escobar GM
et al Anxiety memory impairmentand loco-motor dysfunction caused by a mutant thyr-oid hormone receptor alpha1 can beameliorated by T3 treatment Genes Dev2005192152ndash 63
[37] Pilhatsch M
Winter C
Nordstrom K Venn-strom B Bauer M
Juckel G Increaseddepressive behaviour in mice harboring themutant thyroid hormone receptor alpha 1Behav Brain Res 2010214187ndash 92
[38] Kapoor R
van Hogerlinden M
Wallis KGhosh H Nordstrom K Vennstrom Bet al Unliganded thyroid hormone receptoralpha1 impairs adult hippocampal neurogen-esis FASEB J 2010244793ndash 805
[39] Bassett JH Boyde A Zikmund T Evans HCroucher PI
Zhu X
et al
Thyroid hormonereceptor alpha mutation causes a severe
andthyroxine-resistant skeletaldysplasiain femalemice Endocrinology 20141553699ndash 712
[40] Mittag J Davis B Vujovic M Arner AVennstromB Adaptations of theautonomousnervous system controlling heart rate areimpairedby amutant thyroid hormone recep-tor-alpha1 Endocrinology 20101512388ndash 95
[41] Tavi P Sjogren M Lunde PK Zhang SJAbbate F
Vennstrom B et al Impaired
Ca2+ handling and contraction in cardiomyo-cytes from mice with a dominant negativethyroid hormone receptor alpha1 J Mol CellCardiol 200538655ndash 63
[42] Mittag J Lyons DJ Sall strom J Vujovic MDudazy-Gralla S Warner A
et al Thyroid
hormone is required for hypothalamic neu-rons regulating cardiovascular functions J ClinInvest 2013123509ndash 16
[43] Warner A RahmanA Solsjo P Gottschling KDavis B Vennstrom B et al Inappropriateheatdissipation ignitesbrown fat thermogen-esis in mice with a mutant thyroid hormonereceptor alpha1 Proc Natl Acad Sci U S A201311016241ndash 46
[44] SjogrenM AlkemadeA
MittagJ
NordstromK KatzA Rozell B etal Hypermetabolisminmice caused by the central action of an unli-ganded thyroid hormone receptor alpha1EMBO J 2007264535ndash 45
[45] Ying H Araki O Furuya F Kato Y Cheng SYImpaired adipogenesis caused by a mutated
thyroid hormone alpha1 receptor Mol CellBiol 2007272359ndash 71
[46] Araki O
Ying H Zhu XG Willingham MCChengSY Distinct dysregulationof lipid meta-bolismbyunligandedthyroid hormone recep-tor isoforms Mol Endocrinol 200923308ndash 15
[47] Liu YY
Heymann RS Moatamed F
Schultz JJSobel D Brent GA A mutant thyroid hor-mone receptor alphaantagonizesperoxisomeproliferator-activated receptor alpha signalingin vivo and impairs fatty acid oxidation Endo-crinology 20071481206ndash 17
[48] Fozzatt i L Lu C
Kim DW Cheng SY Differ-ential recruitment of nuclear coregulatorsdirects the isoform-dependent action ofmutant thyroid hormonereceptorsMol Endo-crinol 201125908
ndash 21
[49] Fozzatti
L Kim
DW
ParkJW Willingham
MCHollenberg AN Cheng SY Nuclear receptorcorepresso r (NCOR1) regulates in vivoactions ofa mutated
thyroid
hormone recep-tor alpha Proc Natl
Acad
Sci U S A20131107850ndash 5
[50] Kim DW ParkJW
Willingham MC Cheng SYA histone deacetylase inhibitor improveshypothyroidism caused by a TRalpha1mutant Hum Mol Genet 2014232651ndash 64
V Vlaeminck-Guillem S Espiard F Flamant J-LWeacutemeau
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dimers They are capable of binding on theDNA specific targetsequences (thyroid
hormone response elements
or
TREs)which are located in the regulatory sequences (promotersenhancers) of
the target
genes Like the other
nuclear
recep-tors they in fact behave like ligand-inducible transcription
factors In the absence of hormones and through interactionwith cofactors that repress their transcriptional activity (core-pressors) the
TR reduces
the expression
of
the target
genesLigandbindingenables the TR to releasecorepressors to
recruitactivating partners of transcription (coactivators) and to theninduce
the transcription
of
the target
genes
To
fulfil all
thesefunctions (DNA-binding hormone binding transactivationactivity) the TRs are
organized
into
modules an
N -terminustransactivation domain a DNA-binding domain (DBD) a hingedomain
and a
ligand-binding domain
(LBD) Organized
as
asuccession
of
12
helices this last domain
has on
its C -terminusthe transactivation domain the activity of which is exerted in
the presence
of
the ligand
Indeedmodifications
of
the recep-tor structure occur during hormone binding and involve moreparticularly the 12th helix (H12) which includes the last C -terminus amino acidsIn
the
b
form
of
RTH
the
abnormality
is
carried
by
the
THRB
gene
The
mutations
are
essentially
distributed
over
the
LBD
andthe hinge domain (they do not affect the DNA-binding domainor
the
N -terminus
transactivation
domain)
(1047297 gure
1)
Threeregions rich in cytosine and guanine clusters (CpG islands)are particularly subject to genetic abnormalities (hot spots)[1]
even
though
some
mutations
have
been
reported
outsideof
these
hot
spots
[25] The
two functional
isoforms
producedfrom the THRB gene differing at their N -terminus (TRb1 andTRb2) are both concerned by these
C -terminus abnormalitiesDNA
binding
is
preserved
and
classically
the
mutated
receptorshave a reduced or absence of affinity for T3 They can also havenormal affinity for T3 but a constitutional inability to interactwith
coactivators
[1]
The
phenotype
is
expressed
while
a
singlecopy of the gene is usually involved (heterozygous mutation)The explanation lies in a dominant negative activity exerted bythe mutant receptors on the still functional isoforms By dime-rizing
with
them
they
prevent
the
release
of
the
corepressorsthe recruitment of the coactivators and finally transcriptionalactivity In 90 of cases the identified mutations are missensepoint
mutations
(a
nucleotide
base
is
changed
into
another
resulting
in
an
amino
acid
substitution
on
the
protein
[1])Sometimes
the
point
mutation
is
a
nonsense
mutation
(whichstops protein translation) it may involve the deletion or inser-tion
of
a
nucleotide
base
which
then
leads
to
a
modification
ofthe reading frame and translation of the genetic message intoan erroneous protein message In the case of nonsense muta-tions
or
modifications
of
the
reading
frame
the
affected
recep-tors are truncated on a more or less long part of their
C -terminusCurrently
close
to
500
families
have
thus
been
identified
ascarriers of a THRB gene abnormality and close to 200 different
mutations have been identified (the same mutation may becarried by several different families) [1]As
of
now
there
are
8
known
different
mutations
affecting
theTHRA gene in patients with RTHa (table III ) As with THRB theyare located in the ligand-binding domain (1047297 gure
2) They alsoinvolve
point
mutations
(missense
or
nonsense)
or
abnormali-ties (insertion or deletion of a nucleotide) that result in modifi-cation of the reading frame thus causing a truncated receptorAs with RTHb point mutations seem to be predominant (6 out of8
times)
These
were
de
novo
mutations
in
6
patients
In4 patients the abnormality occurred through autosomal domi-nant transmission by an affected parent (father or mother)Contrary
to
isoforms
TRb1 and
TRb2
which
differ
on
their
N -
terminus
the
main
isoforms
produced
from
the
THRA
geneTRa1
and
TRa2
differ
on
their
C -terminus
They
share
a
commonprotein sequence up until the 360th amino acid the sequencesthen
diverge
resulting
in
a
functional
LBD
for
TRa1
and
an
LBDthat is incapable of binding T3 for TRa2 Six of the eight abnor-malities detected are located in the part of the gene concerningonly
TRa1 [14ndash161920] the
two
others
concern
the
commonsequence between TRa1 and TRa2 [1721] Several of themutations
identified
in
the
THRA
gene
in
cases
of
RTHa
werealso identified in the THRB gene in cases of RTHb A263V (THRA)
Figure
1
The
main
isoforms
produced
by
the
THRB
gene
and
themutations
described
in
the
b
form
of
resistance
to
thyroid
hormonesThe isoforms TRb1 and TRb2 are functional receptors capable of binding DNA and T3
and
influencing under the control of the latter the expression of target genes The
mutations found in RTHb are concentrated in the T3 binding domain (E)and thehinge
domain (D) which separates it from the DNA-binding domain (C) and theN -terminus
transactivation domain (AB) Theyare present in the common sequenceof isoforms
TRb1
and TRb2 Three areas are particularly sensitive to mutations (hot spots) and
are foundbetween aminoacids234and 282 ( 1) 309 and 353 ( 2) and 426 and
460 ( 3 numbering in 461 amino acids of the TRb1
receptor)
TRa
receptor mutations extend the spectrum of syndromes of reduced sensitivity tothyroid hormone ENDOCRINOLOGIE
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and
A317V
(THRB) [17] R384C
and
R438C
[1926] C392X
andC446X
mutations
[2027] Modification
of
the
reading
framefrom amino acid 382 in TRa1 (due to the insertion of a nucleo-tide base in the
THRA gene) [15] has also been reported in the
equivalent
residue
of
TRb1TRb2 (insertions
of
several
bases
inthe THRB gene) [28] although the erroneous consecutivesequence is not the same For the other
THRA gene mutations
with
no
strict
equivalent
in
the
THRB
gene
similar
mutationshave been described either resulting in another substitution oroccurring in a neighbouring residue One notable exceptionhowever is the N359Y mutation [21] which has no strictequivalent
and
in
which
the
corresponding
amino
acid
in
theTRb1TRb2 sequence is not in one of the three known hotspots (a partial explanation for this may lie in the distinctivefeatures
of
the
phenotype
associated
with
this
mutation
see
below)
In
any
case
comparison
of
the a
and b
forms
of
RTH
foridentical
or
equivalent
mutations
enables
the
respective
rolesof the different receptors to be specified In general then the b
receptors
seem
to
be
clearly
involved
in
the
hypothalamic-pituitary feedback loop while the a receptors are more involvedin the peripheral effects of THSeveral
TRa1 mutants
have
been
examined
in
functional
stud-ies Their common points include their incapability to induce theexpression
of
target
genes
and
their
dominant
negative
repres-sor activity over the normal TRa1 receptor [14ndash172129] When
it
was
evaluated
the
affinity
for
T3
was
reduced
[161721]Moreover
the
dominant
negative
activity
seems
to
be
exertedon the TRb1 receptor [152129] The still small number ofreported cases does not enable the formulation of genotypendashphenotype
correlations
For
example
only
two
mutations
affectboth TRa1 and TRa2 While the A263V mutation does not resultin a phenotype different from that observed for mutations thatonly
affect
TRa1 [17]the
phenotype
associated
with
the
N359Ymutation is particular due to the incidence (coincidental) of amarked malformation syndrome and hypercalcemia from para-thyroid hyperplasia and even to the absence of constipation andintellectual
deficit
(though
this
absence
has
also
been
observedin other cases) [21] Whether other isoforms produced from theTHRA
gene (TRa3 p43 P30 TRD1 and TRD2) are implicated inthe
phenotype
also
deserves
to
be
explored
[21] Although
this
needs
to
be
substantiated
with
subsequent
clinical
cases
thereis
a
tendency
for
more
serious
forms
to
exist
with
the
mutationoccurring early in the sequence and resulting in truncation Themost
significant
intellectual
deficit
(IQ
of
22)
was
described
forthe mutation involving the 18 amino acid deletion of TRa1 [20]Conversely patients with normal IQs are carriers of missensepoint
mutations
that
only
substitute
one
amino
acid
for
another[2021] In RTHb the severe forms are also often related toTRb1TRb2
truncations
[28] It
is
likely
that
truncations
(result-ing in the lack of C -terminal helix 12) induce more severe
TABLE IIIDescription
of
the
known
mutations
in
THRA
gene
(encoding
the
thyroid
hormone
receptor
TRa1)
in
patients
with
the a
syndrome
of
resistance
to
thyroid
hormone
Protein
mutation1
Number of
involvedfamilies
Number of
involvedpatients
THRA gene mutations2 Type of protein
mutation
Consequences for protein
functions
Involved
isoforms
References
A263V 1 3 Single base substitution (CxxxxT) Missense Single aminoacid substitution TRa1TRa2
[17]
N359Y 1 1 Single base substitution (C1075G) Missense Single aminoacid substitution TRa1TRa2
[21]
A382fs388X 1 1 Single base deletion(1144delG)
Frameshift Wrong sequence from A382then premature truncation at
position 388
TRa1 [16]
R384C 1 1 Single base substitution (C1150 T) Missense Single aminoacid substitution TRa1 [19]
C392X 1 1 Single base substitution (C1176A) No-sense Premature truncation atposition C392
TRa1 [20]
F397fs406X 1 2 Single base insertion(1144insT) Frameshift
Wrong sequence from F397then premature truncation atposition 406
TRa1 [1518]
P398R 1 1 Single base substitution (C1150 T) Missense Single aminoacid substitution TRa1 [20]
E403X 3 4 Single base substitution (C1176A) No-sense Premature truncation atposition E403
TRa1 [1420]
1The numbering is based on the TRa1 protein sequence (common to the TRa2 sequence until the amicoacid 360)2All mutations are located in exon 9 of the THRA gene (last exon of TRa1 and the secondlast for TRa2)
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Figure 2
The
main
isoforms
produced
by
the
THRA
gene
and
the
mutations
described
in
the
a
form
of
resistance
to
thyroid
hormonesIsoform TRa1 isa functional receptor capable of binding DNA and T3 and influencingunder thecontrolof thelatter theexpression of target genes Isoform TRa2
is incapable of
binding thehormoneand behaves like a weak dominant negative inhibitor of the T3 functionalreceptorsFor now themutations found in RTHa rein the T3 binding domain (E)
while
thehinge domain(D) theDNA-binding domain (C)and theN -terminus transactivation domain (AB) arespared Themutationsconcern the commonsequence of thetwo
isoforms TRa1andTRa2 oronlyaffectthe C -terminussequence of TRa1 (numbering in410 amino acids ofthe TRa1 receptor) Thepoint mutations arerepresentedby a star and
the
frameshift mutations by a star at the level of the first mutated amino acid fol lowed by a blue box representing the modified sequence
The four mutations introduced in the THRA gene to try to generate murine models of the a form of resistance to thyroid hormones are also indicated in italic font (R384C
P394fs406X P398H and L400R) The numbering for the murine isoform TRa1
is the same as for the human isoform
TRa receptor mutations extend the spectrum of syndromes of reduced sensitivity tothyroid hormone ENDOCRINOLOGIE
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phenotype by profoundly affecting TR function through totalinability
to
interact
with
coactivatorsThe genotypendashphenotype correlations may in fact need to beinvestigatedin
animal
modelsMicewith
complete
inactivationof the THRA andor
THRB genes have been reported [11] but
may not represent the most relevant models as the absence ofa receptor does nothave the same consequences as the expres-sion
of
an
abnormal receptor
The comparison
is
more
logical inanimal
models
with
an
artificially
introduced
mutation For theTHRA
gene thereare fourdifferentmodels available that are allbased
on
a
mutation
of
the hormone-binding domain in
onlythe TRa1 receptor (1047297 gure 2 no model with mutation affectingTRa1
and TRa2)
One model
introduced
in
TRa1 the PV
muta-tion [13] which was identified in a patientwith RTHb (insertionof
several
nucleotides
with
modification of
the reading
frame)[30]
while
the others
introduce
point
mutations
R384C
[29](corresponding exactly to a
THRA mutation in a patient with
RTHa
[19])
L400R
[31]
and P398H
[32] These models
providephenotypic data that are complementary to those reported inhuman cases The growth retardation with impairment in ossi-fication is consistent in all animals [132931ndash34] The role ofTRa1
in
the development
of
chondrocytes
is probably a
deter-mining factor
as
the
elective introduction
of
the
L400R
muta-tion in the chondrocytes is sufficient to induce the phenotype[35]
The severity
of
the bone phenotype however
is
variabledepending on the models The bone phenotype of the R384Cmutation for instance was observed in young mice and dis-appeared in
the adultmice
[29]
In humans this
mutationwasreported in
a
girl though
it
is
only
known that
she
was
a
carrierof a familial form of autism without other information on herphenotype It is interesting to observe that the R384C mice hadsignificant psychomotor
disorders
with
anxiety memoryimpairment and depression (which are possible even fre-quent manifestations of autism) [3637] Cerebellar ataxiawas
also
observed
in
another
model
[31]
which
is
somewhatsimilar to the clumsiness and awkwardness described in thegait or the handling of objects in several patients with RTHa[141617] In animals these psychoneuromotor disorders arerelated
to impairment
of
neurogenesis
in
the hippocampus(lack of certain GABAergic interneurons) [38] and diminishpartially with levothyroxine [3638] This reduction on treat-ment
is not
observed
for the
bone
phenotype [39] as
was
also
reported in
humans Another
common
point of
the animalmodels
with
TRa1 mutations
is the
near-normality
of
TH
serumlevels On the other hand TSH has been found to be high inseveral
models
[1332]
as
opposed to its usual observed nor-mality in patients with RTHa (high-normal values in one case[16]) The T4T3 ratio and the reverse T3 (rT3) found to be lowin
patients with
RTHa
are
considered
an
indication of
theperipheral metabolism of TH Interestingly high levels of type1
deiodinase
(responsible for the conversion
of
T4
into
T3 andfor the clearance of rT3)have been measured in the liver of one
of the murine models [13] Normal levels were however
detected
in
another [31]Investigations of murine models found bradycardia [293132]which
was
rather
mild
but
accompanied
by
inadaptation
tostress [40] Bradycardia was reported in patients with RTHa
[141617] but the rare functional heart explorations that weredone did not demonstrate serious abnormalities [16] Bradycar-dia
is
probably
the
result
of
the
direct
effect
of
TH
on
themyocardium
(known
target
tissue
of
TH
expressing
ratherTRa1) abnormalities of calcium flux and contractility wereobserved
in
one
model
[41] However
there
is
probably
anothermechanism involved namely deregulation of the autonomicnervous
system
due
to
abnormal
brain
development
[4042]The same mechanism (lack of cerebral control on the autonomicnervous
system)
has
been
suggested
as
an
explanation
forthermogenesis
abnormalities
These
abnormalities
have
notbeen actually reported (not explored) in patients with RTHa
A
reduction
in
body
temperature
andor
a
cold
intolerance
wasdescribed in two murine models [3132] Dysfunction of thebrown fat is suspected related to deregulation of the autonomicnervous system caused by abnormal brain development [38]Increased
vasodilatation
again
related
to
the
autonomic
ner-vous
system
was
supposedly
also
observed
in
one
of
the
mo-dels with abnormal thermogenesis [43]One
patient
with
RTHa
had
weight
loss
(occurring
in
childhoodand continuing in adulthood) [21] while the other patients hadnormal or increased weight [15ndash18] One murine model exhib-ited
overweight
(without
increased
food
intake)
hepatic
stea-tosis
and
insulin
resistance
[32] but
a
controversy
exists
aboutthe real responsibility of THRA mutation Two others models hadhyperphagia without weight gain resistance to tube-feedingmild
adiposity
due
to
impairment
of
adipogenesis
and
low
liverconcentrations of lipids [44ndash46] The same mechanism aninteraction with PPARg has been suggested in both of thesecontrary
situations
[4547]
ConclusionsTowards the end of the 1980s the first descriptions of abnor-malities of the
THRB gene in patients with RTHb generated a
very
large
number
of
questions
about
the
possibility
of
muta-tions
in
the
THRA
gene
Answers
have
arrived
more
than
20
yearslater with the description of clinical phenotypes that are quite
particular
abnormalities
suggestive
of
mild
untreated
congeni-tal hypothyroidism in conjunction with thyroid function teststhat are more or less normal and therefore discordant For themoment
suggestive
symptoms
are
short
stature
hypothyroid-ism-like
facial
shape
and
low
T4T3
ratio
It
is
worthy
to
notethat
the
whole
exome
database
(httpexacbroadinstituteorg) contains 68
THRA missense or frameshift mutations with
most
of
them
predicted
to
alter
TRa1 function
It
is
thereforelikely that several patients in the general population haveundiagnosed RTHa with milder phenotype As in RTHb it is
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the discordance between the clinical and the laboratory datathat
should
stand
out
for
the
clinician
The
identification
ofpatients with authenticated abnormalities of the
THRA gene
is
essential
for
improving
the
definition
of
the
clinical
spectrumof RTHa and more generally of all RTH and syndromes of
reduced sensitivity to thyroid hormones This improved pheno-typic definition will enable genotypendashphenotype correlations tobe
formulated
and
perhaps
the
development
of
therapeuticguidelines
The
reported
cases
show
that
the
administrationof TH in patients with RTHa does not improve all the symptomsprobably
because
the
therapeutic
management
occurs
too
latefor certain abnormalities that have already become definitivelyestablished
andor
because
the
tissue
resistance
is
too
severeThe extreme dependence for TH during the brain development isa
clear
example
of
the
need
for
early
treatment
The
significance
of this seems to depend partially on the nature of the underlyinggenetic
abnormality
The
different
murine
models
with
diversegenetic abnormalities may thus be valuable tools for testing thetherapeutic
approaches
Assuming
that
the
resistance
is
toosevere to be managed by hormonal treatment identification
of the major role in animals of the interaction of mutated TRa1with corepressors such as NCoR [48] was crucial Indeed it ledto
the
demonstration
of
the
partial
reversal
of
the
abnormalTHRA
gene
phenotype
through
the
coexpression
of
a
mutantNCoR unable to interact with the TRs [49] and through theadministration
of
an
inhibitor
of
the
corepressors-associatedhistone deacetylase activity [50]
Disclosure of interest the authors declare that they have no conflicts ofinterest concerning this article
References[1] Dumitrescu AM Refetoff S The syndromes
of reduced sensitivity to thyroid hormoneBiochim Biophys Acta 201318303987ndash 4003
[2] Refetoff S DeWind LT
DeGroot LJ Familialsyndrome combining deaf-mutism stuppledepiphyses goiter and abnormally high PBIpossible target organ refractoriness to thyroidhormone J Clin Endocrinol Metab196727279ndash 94
[3] Sakurai A TakedaK Ain K Ceccarelli P NakaiA Seino S et al Generalized resistance tothyroid hormone associated with a mutationin the ligand-binding domain of the humanthyroid hormone receptor beta Proc Nat l
Acad Sci U S A 1989868977ndash 81
[4] Vlaeminck-Guillem V Margotat A Torresani J DHerbomez M Decoulx M Wemeau JLResistance to thyroid hormone in a familywith no TRbeta gene anomaly pathogenichypotheses Ann Endocrinol (Paris)200061149ndash 94
[5] Weiss RE
Hayashi Y
Nagaya T
Petty KJMurata Y Tunca H et al Dominant inheri-tance of resistance to thyroid hormone notlinked to defects in the thyroid hormonereceptor alpha or beta genes may be dueto a defective cofactor J Clin EndocrinolMetab1996814196ndash 203
[6] Pohlenz J Weiss RE
Macchia PE Pannain SLau IT Ho H et al Five new families with
resistance to thyroid hormone not caused bymutations in the thyroid hormone receptorbeta gene J Clin Endocrinol Metab1999843919ndash 28
[7] DumitrescuAM Liao XH Abdullah MS Lado-Abeal J Majed FA Moeller LC et al Muta-tions in SECISBP2 result in abnormal thyroidhormone metabolism Nat Genet2005371247ndash 52
[8] Dumitrescu AM Liao XH Best TB Brock-mann K Refetoff S A novel syndromecombining thyroid and neurological
abnormalities is associated with mutationsin a monocarboxylate transporter gene Am J Hum Genet 200474168ndash 75
[9] Friesema EC Grueters A
Biebermann HKrude H von Moers A Reeser M et alAssociation between mutations in a thyroidhormone transporter and
severe X-linked psy-chomotor retardation Lancet 20043641435ndash 7
[10] Refetoff S Bassett JH
Beck-Peccoz P Bernal JBrent G Chatterjee K et al Classificationandproposednomenclaturefor inheriteddefects ofthyroid hormone action cell transport andmetabolism Eur Thyroid J 201437ndash 9
[11] Vlaeminck-Guillem V Wemeau JL
Physiolo-gie et physiopathologie des reacutecepteurs thyr-oiumldiens lapport des modegraveles murins AnnEndocrinol (Paris) 200061440ndash 51
[12] Wikstrom L Johansson C Salto C Barlow CCampos Barros A Baas F et al Abnormalheart rate and body temperature in micelacking thyroid hormone receptor alpha 1EMBO J 199817455ndash 61
[13] Kaneshige M Suzuki H Kaneshige K Cheng J Wimbrow H Barlow C et al A targeteddominant negative mutation of the thyroidhormone alpha 1 receptor causes increasedmortality infertility and dwarfism in miceProc Natl Acad Sci U S A 20019815095ndash 100
[14] Bochukova E Schoenmakers N Agostini M
Schoenmakers E RajanayagamO Keogh JMet al A mutation in the thyroid hormonereceptor alpha gene N Engl J Med2012366243ndash 9
[15] van Mullem A van Heerebeek R Chrysis DVisser E Medici M Andrikoula M et alClinical phenotype and mutant TRalpha1 NEngl J Med 20123661451ndash 3
[16] Moran C
Schoenmakers N Agostini MSchoenmakers E Offiah A
Kydd
A et alAn adult female with resistance to thyroidhormone mediated by defective thyroid
hormone receptor alpha J Cl in EndocrinolMetab 2013984254ndash 61
[17] Moran C Agostini M Visser WE Schoen-makers E SchoenmakersN Offiah AC etalResistance to thyroid hormone caused by amutation in thyroid hormone receptor (TR)alpha1 and
TRalpha2 clinical biochemicaland genetic analyses
of three
related patientsLancet Diabet Endocrinol 20142619ndash 26
[18] van Mullem AA Chrysis D Eythimiadou AChroni E Tsatsoulis A de Rijke YB et alClinical phenotype of a new type of thyroidhormone resistance caused by a mutation ofthe TRalpha1 receptor consequences of LT4
treatment J Clin Endocrinol Metab2013983029ndash 38
[19] Yuen RK Thiruvahindrapuram B Merico DWalker S Tammimies K Hoang N et alWhole-genome sequencing of quartetfamilies with autism spectrum disorder NatMed 201521185ndash 91
[20] Tylki-Szymanska A Acuna-Hidalgo R Kra- jewska-Walasek M Lecka-Ambroziak ASteehouwer M Gi lissen C et al Thyroidhormone resistance syndrome due to muta-tions in the thyroid hormone receptor alphagene (THRA) J Med Genet 201552312ndash 6
[21] Espiard S Savagner F
Flamant F
Vlaeminck-Guillem V Guyot R Munier M
et al A novelmutation in THRA gene associated with an
atypical phenotype of resistance to thyroidhormone J Clin Endocrinol Metab 2015 jc20151120
[22] Faivre L Cormier-Daire V GenevieveD PintoG Goulet O
Munnich A
et al A novelsyndrome with dwarfism poorly muscledbuild absent clavicles humeroradial fusionslender bones oligodactyly and micro-gnathia Clin Dysmorphol 200110181ndash 4
[23] Mundlos S Cleidocranial dysplasia clinicaland molecular genetics J Med Genet199936177ndash 82
TRa receptor mutations extend the spectrum of syndromes of reduced sensitivity tothyroid hormone ENDOCRINOLOGIE
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[24] Mundlos S Otto F
Mundlos C Mulliken JBAylsworth AS Albright S et a l Mutat ionsinvolving the transcription factor CBFA1
causecleidocranial dysplasia Cell 199789773ndash 9
[25] Margotat A
Sarkissian G Malezet-Desmou-lins C Peyrol N Vlaeminck Guillem V
Wemeau JL
et al Ident if ication of eightnew mutations in the c-erbAB gene ofpatients with resistance to thyroid hormoneAnn Endocrinol 200162220ndash 5
[26] Adams M Matthews C Coll ingwood TNToneY
Beck-Peccoz P ChatterjeeKK Geneticanalysis of 29 kindreds with generalized andpituitary resistance to thyroid hormone Iden-tification of thirteen novel mutations in thethyroid hormone receptor beta gene J ClinInvest 199494506ndash 15
[27] Groenhout EG Dorin RI Generalized thyroidhormone resistance due to a deletion of thecarboxy terminus of the c-erbA beta receptorMol Cell Endocrinol 19949981ndash 8
[28] Wu SY CohenRN SimsekE Senses DA Yar
NE Grasberger H et al A novel thyroidhormone receptor-beta mutation that failsto bind nuclear receptor corepressor in apatient as an apparent cause of severe pre-dominantly pituitary resistance to thyroid hor-mone J Clin Endocrinol Metab 2006911887ndash 95
[29] Tinnikov A Nordstrom K Thoren P Kindblom JM Malin S Rozell B et al Retardation ofpost-natal development caused by a nega-tively acting thyroid hormone receptoralpha1 EMBO J 2002215079ndash 87
[30] Parrilla R
Mixson AJ McPherson JA
McClas-key JH Weintraub BD Characterization ofseven novel mutations of the c-erbA betagene in unrelated kindreds with generalizedthyroidhormone resistance Evidence for twohot spot regions of the l igand bindingdomain J Clin Invest 1991882123ndash 30
[31] Quignodon L VincentS Winter H Samarut JFlamant F A point mutation in the
activationfunction2 domainof thyroidhormonereceptoralpha1 expressed after CRE-mediated recom-bination partially recapitulates hypothyroid-ism Mol Endocrinol 2007212350ndash 60
[32] Liu YY
Schultz JJ
Brent GA A thyroidhormone receptor alpha gene mutation
(P398H) is associated with visceral adiposityand impaired catecholamine-stimulated lipo-lysis in mice J Biol Chem 200327838913ndash 20
[33] OShea PJ Bassett JH ChengSY Williams GRCharacterization of skeletal phenotypes ofTRalpha1 and TRbeta mutant mice implica-
tions for tissue thyroid status and T3 targetgene expression Nucl Recept Signal 20064e011
[34] OShea PJ Bassett JH Sriskantharajah S YingH Cheng SY Williams GR Contrasting ske-leta l phenotypes in mice with an identicalmutation targeted to thyroid hormone recep-tor alpha1 or beta Mol Endocrinol2005193045ndash 59
[35] Desjardin C
Charles C
Benoist-Lasselin CRiviere J Gilles M Chassande O et alChondrocytes play a major role in the stimu-lation of bone growth by thyroid hormoneEndocrinology 20141553123ndash 35
[36] Venero C Guadano-Ferraz A Herrero AINordstrom K Manzano J de Escobar GM
et al Anxiety memory impairmentand loco-motor dysfunction caused by a mutant thyr-oid hormone receptor alpha1 can beameliorated by T3 treatment Genes Dev2005192152ndash 63
[37] Pilhatsch M
Winter C
Nordstrom K Venn-strom B Bauer M
Juckel G Increaseddepressive behaviour in mice harboring themutant thyroid hormone receptor alpha 1Behav Brain Res 2010214187ndash 92
[38] Kapoor R
van Hogerlinden M
Wallis KGhosh H Nordstrom K Vennstrom Bet al Unliganded thyroid hormone receptoralpha1 impairs adult hippocampal neurogen-esis FASEB J 2010244793ndash 805
[39] Bassett JH Boyde A Zikmund T Evans HCroucher PI
Zhu X
et al
Thyroid hormonereceptor alpha mutation causes a severe
andthyroxine-resistant skeletaldysplasiain femalemice Endocrinology 20141553699ndash 712
[40] Mittag J Davis B Vujovic M Arner AVennstromB Adaptations of theautonomousnervous system controlling heart rate areimpairedby amutant thyroid hormone recep-tor-alpha1 Endocrinology 20101512388ndash 95
[41] Tavi P Sjogren M Lunde PK Zhang SJAbbate F
Vennstrom B et al Impaired
Ca2+ handling and contraction in cardiomyo-cytes from mice with a dominant negativethyroid hormone receptor alpha1 J Mol CellCardiol 200538655ndash 63
[42] Mittag J Lyons DJ Sall strom J Vujovic MDudazy-Gralla S Warner A
et al Thyroid
hormone is required for hypothalamic neu-rons regulating cardiovascular functions J ClinInvest 2013123509ndash 16
[43] Warner A RahmanA Solsjo P Gottschling KDavis B Vennstrom B et al Inappropriateheatdissipation ignitesbrown fat thermogen-esis in mice with a mutant thyroid hormonereceptor alpha1 Proc Natl Acad Sci U S A201311016241ndash 46
[44] SjogrenM AlkemadeA
MittagJ
NordstromK KatzA Rozell B etal Hypermetabolisminmice caused by the central action of an unli-ganded thyroid hormone receptor alpha1EMBO J 2007264535ndash 45
[45] Ying H Araki O Furuya F Kato Y Cheng SYImpaired adipogenesis caused by a mutated
thyroid hormone alpha1 receptor Mol CellBiol 2007272359ndash 71
[46] Araki O
Ying H Zhu XG Willingham MCChengSY Distinct dysregulationof lipid meta-bolismbyunligandedthyroid hormone recep-tor isoforms Mol Endocrinol 200923308ndash 15
[47] Liu YY
Heymann RS Moatamed F
Schultz JJSobel D Brent GA A mutant thyroid hor-mone receptor alphaantagonizesperoxisomeproliferator-activated receptor alpha signalingin vivo and impairs fatty acid oxidation Endo-crinology 20071481206ndash 17
[48] Fozzatt i L Lu C
Kim DW Cheng SY Differ-ential recruitment of nuclear coregulatorsdirects the isoform-dependent action ofmutant thyroid hormonereceptorsMol Endo-crinol 201125908
ndash 21
[49] Fozzatti
L Kim
DW
ParkJW Willingham
MCHollenberg AN Cheng SY Nuclear receptorcorepresso r (NCOR1) regulates in vivoactions ofa mutated
thyroid
hormone recep-tor alpha Proc Natl
Acad
Sci U S A20131107850ndash 5
[50] Kim DW ParkJW
Willingham MC Cheng SYA histone deacetylase inhibitor improveshypothyroidism caused by a TRalpha1mutant Hum Mol Genet 2014232651ndash 64
V Vlaeminck-Guillem S Espiard F Flamant J-LWeacutemeau
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and
A317V
(THRB) [17] R384C
and
R438C
[1926] C392X
andC446X
mutations
[2027] Modification
of
the
reading
framefrom amino acid 382 in TRa1 (due to the insertion of a nucleo-tide base in the
THRA gene) [15] has also been reported in the
equivalent
residue
of
TRb1TRb2 (insertions
of
several
bases
inthe THRB gene) [28] although the erroneous consecutivesequence is not the same For the other
THRA gene mutations
with
no
strict
equivalent
in
the
THRB
gene
similar
mutationshave been described either resulting in another substitution oroccurring in a neighbouring residue One notable exceptionhowever is the N359Y mutation [21] which has no strictequivalent
and
in
which
the
corresponding
amino
acid
in
theTRb1TRb2 sequence is not in one of the three known hotspots (a partial explanation for this may lie in the distinctivefeatures
of
the
phenotype
associated
with
this
mutation
see
below)
In
any
case
comparison
of
the a
and b
forms
of
RTH
foridentical
or
equivalent
mutations
enables
the
respective
rolesof the different receptors to be specified In general then the b
receptors
seem
to
be
clearly
involved
in
the
hypothalamic-pituitary feedback loop while the a receptors are more involvedin the peripheral effects of THSeveral
TRa1 mutants
have
been
examined
in
functional
stud-ies Their common points include their incapability to induce theexpression
of
target
genes
and
their
dominant
negative
repres-sor activity over the normal TRa1 receptor [14ndash172129] When
it
was
evaluated
the
affinity
for
T3
was
reduced
[161721]Moreover
the
dominant
negative
activity
seems
to
be
exertedon the TRb1 receptor [152129] The still small number ofreported cases does not enable the formulation of genotypendashphenotype
correlations
For
example
only
two
mutations
affectboth TRa1 and TRa2 While the A263V mutation does not resultin a phenotype different from that observed for mutations thatonly
affect
TRa1 [17]the
phenotype
associated
with
the
N359Ymutation is particular due to the incidence (coincidental) of amarked malformation syndrome and hypercalcemia from para-thyroid hyperplasia and even to the absence of constipation andintellectual
deficit
(though
this
absence
has
also
been
observedin other cases) [21] Whether other isoforms produced from theTHRA
gene (TRa3 p43 P30 TRD1 and TRD2) are implicated inthe
phenotype
also
deserves
to
be
explored
[21] Although
this
needs
to
be
substantiated
with
subsequent
clinical
cases
thereis
a
tendency
for
more
serious
forms
to
exist
with
the
mutationoccurring early in the sequence and resulting in truncation Themost
significant
intellectual
deficit
(IQ
of
22)
was
described
forthe mutation involving the 18 amino acid deletion of TRa1 [20]Conversely patients with normal IQs are carriers of missensepoint
mutations
that
only
substitute
one
amino
acid
for
another[2021] In RTHb the severe forms are also often related toTRb1TRb2
truncations
[28] It
is
likely
that
truncations
(result-ing in the lack of C -terminal helix 12) induce more severe
TABLE IIIDescription
of
the
known
mutations
in
THRA
gene
(encoding
the
thyroid
hormone
receptor
TRa1)
in
patients
with
the a
syndrome
of
resistance
to
thyroid
hormone
Protein
mutation1
Number of
involvedfamilies
Number of
involvedpatients
THRA gene mutations2 Type of protein
mutation
Consequences for protein
functions
Involved
isoforms
References
A263V 1 3 Single base substitution (CxxxxT) Missense Single aminoacid substitution TRa1TRa2
[17]
N359Y 1 1 Single base substitution (C1075G) Missense Single aminoacid substitution TRa1TRa2
[21]
A382fs388X 1 1 Single base deletion(1144delG)
Frameshift Wrong sequence from A382then premature truncation at
position 388
TRa1 [16]
R384C 1 1 Single base substitution (C1150 T) Missense Single aminoacid substitution TRa1 [19]
C392X 1 1 Single base substitution (C1176A) No-sense Premature truncation atposition C392
TRa1 [20]
F397fs406X 1 2 Single base insertion(1144insT) Frameshift
Wrong sequence from F397then premature truncation atposition 406
TRa1 [1518]
P398R 1 1 Single base substitution (C1150 T) Missense Single aminoacid substitution TRa1 [20]
E403X 3 4 Single base substitution (C1176A) No-sense Premature truncation atposition E403
TRa1 [1420]
1The numbering is based on the TRa1 protein sequence (common to the TRa2 sequence until the amicoacid 360)2All mutations are located in exon 9 of the THRA gene (last exon of TRa1 and the secondlast for TRa2)
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Figure 2
The
main
isoforms
produced
by
the
THRA
gene
and
the
mutations
described
in
the
a
form
of
resistance
to
thyroid
hormonesIsoform TRa1 isa functional receptor capable of binding DNA and T3 and influencingunder thecontrolof thelatter theexpression of target genes Isoform TRa2
is incapable of
binding thehormoneand behaves like a weak dominant negative inhibitor of the T3 functionalreceptorsFor now themutations found in RTHa rein the T3 binding domain (E)
while
thehinge domain(D) theDNA-binding domain (C)and theN -terminus transactivation domain (AB) arespared Themutationsconcern the commonsequence of thetwo
isoforms TRa1andTRa2 oronlyaffectthe C -terminussequence of TRa1 (numbering in410 amino acids ofthe TRa1 receptor) Thepoint mutations arerepresentedby a star and
the
frameshift mutations by a star at the level of the first mutated amino acid fol lowed by a blue box representing the modified sequence
The four mutations introduced in the THRA gene to try to generate murine models of the a form of resistance to thyroid hormones are also indicated in italic font (R384C
P394fs406X P398H and L400R) The numbering for the murine isoform TRa1
is the same as for the human isoform
TRa receptor mutations extend the spectrum of syndromes of reduced sensitivity tothyroid hormone ENDOCRINOLOGIE
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phenotype by profoundly affecting TR function through totalinability
to
interact
with
coactivatorsThe genotypendashphenotype correlations may in fact need to beinvestigatedin
animal
modelsMicewith
complete
inactivationof the THRA andor
THRB genes have been reported [11] but
may not represent the most relevant models as the absence ofa receptor does nothave the same consequences as the expres-sion
of
an
abnormal receptor
The comparison
is
more
logical inanimal
models
with
an
artificially
introduced
mutation For theTHRA
gene thereare fourdifferentmodels available that are allbased
on
a
mutation
of
the hormone-binding domain in
onlythe TRa1 receptor (1047297 gure 2 no model with mutation affectingTRa1
and TRa2)
One model
introduced
in
TRa1 the PV
muta-tion [13] which was identified in a patientwith RTHb (insertionof
several
nucleotides
with
modification of
the reading
frame)[30]
while
the others
introduce
point
mutations
R384C
[29](corresponding exactly to a
THRA mutation in a patient with
RTHa
[19])
L400R
[31]
and P398H
[32] These models
providephenotypic data that are complementary to those reported inhuman cases The growth retardation with impairment in ossi-fication is consistent in all animals [132931ndash34] The role ofTRa1
in
the development
of
chondrocytes
is probably a
deter-mining factor
as
the
elective introduction
of
the
L400R
muta-tion in the chondrocytes is sufficient to induce the phenotype[35]
The severity
of
the bone phenotype however
is
variabledepending on the models The bone phenotype of the R384Cmutation for instance was observed in young mice and dis-appeared in
the adultmice
[29]
In humans this
mutationwasreported in
a
girl though
it
is
only
known that
she
was
a
carrierof a familial form of autism without other information on herphenotype It is interesting to observe that the R384C mice hadsignificant psychomotor
disorders
with
anxiety memoryimpairment and depression (which are possible even fre-quent manifestations of autism) [3637] Cerebellar ataxiawas
also
observed
in
another
model
[31]
which
is
somewhatsimilar to the clumsiness and awkwardness described in thegait or the handling of objects in several patients with RTHa[141617] In animals these psychoneuromotor disorders arerelated
to impairment
of
neurogenesis
in
the hippocampus(lack of certain GABAergic interneurons) [38] and diminishpartially with levothyroxine [3638] This reduction on treat-ment
is not
observed
for the
bone
phenotype [39] as
was
also
reported in
humans Another
common
point of
the animalmodels
with
TRa1 mutations
is the
near-normality
of
TH
serumlevels On the other hand TSH has been found to be high inseveral
models
[1332]
as
opposed to its usual observed nor-mality in patients with RTHa (high-normal values in one case[16]) The T4T3 ratio and the reverse T3 (rT3) found to be lowin
patients with
RTHa
are
considered
an
indication of
theperipheral metabolism of TH Interestingly high levels of type1
deiodinase
(responsible for the conversion
of
T4
into
T3 andfor the clearance of rT3)have been measured in the liver of one
of the murine models [13] Normal levels were however
detected
in
another [31]Investigations of murine models found bradycardia [293132]which
was
rather
mild
but
accompanied
by
inadaptation
tostress [40] Bradycardia was reported in patients with RTHa
[141617] but the rare functional heart explorations that weredone did not demonstrate serious abnormalities [16] Bradycar-dia
is
probably
the
result
of
the
direct
effect
of
TH
on
themyocardium
(known
target
tissue
of
TH
expressing
ratherTRa1) abnormalities of calcium flux and contractility wereobserved
in
one
model
[41] However
there
is
probably
anothermechanism involved namely deregulation of the autonomicnervous
system
due
to
abnormal
brain
development
[4042]The same mechanism (lack of cerebral control on the autonomicnervous
system)
has
been
suggested
as
an
explanation
forthermogenesis
abnormalities
These
abnormalities
have
notbeen actually reported (not explored) in patients with RTHa
A
reduction
in
body
temperature
andor
a
cold
intolerance
wasdescribed in two murine models [3132] Dysfunction of thebrown fat is suspected related to deregulation of the autonomicnervous system caused by abnormal brain development [38]Increased
vasodilatation
again
related
to
the
autonomic
ner-vous
system
was
supposedly
also
observed
in
one
of
the
mo-dels with abnormal thermogenesis [43]One
patient
with
RTHa
had
weight
loss
(occurring
in
childhoodand continuing in adulthood) [21] while the other patients hadnormal or increased weight [15ndash18] One murine model exhib-ited
overweight
(without
increased
food
intake)
hepatic
stea-tosis
and
insulin
resistance
[32] but
a
controversy
exists
aboutthe real responsibility of THRA mutation Two others models hadhyperphagia without weight gain resistance to tube-feedingmild
adiposity
due
to
impairment
of
adipogenesis
and
low
liverconcentrations of lipids [44ndash46] The same mechanism aninteraction with PPARg has been suggested in both of thesecontrary
situations
[4547]
ConclusionsTowards the end of the 1980s the first descriptions of abnor-malities of the
THRB gene in patients with RTHb generated a
very
large
number
of
questions
about
the
possibility
of
muta-tions
in
the
THRA
gene
Answers
have
arrived
more
than
20
yearslater with the description of clinical phenotypes that are quite
particular
abnormalities
suggestive
of
mild
untreated
congeni-tal hypothyroidism in conjunction with thyroid function teststhat are more or less normal and therefore discordant For themoment
suggestive
symptoms
are
short
stature
hypothyroid-ism-like
facial
shape
and
low
T4T3
ratio
It
is
worthy
to
notethat
the
whole
exome
database
(httpexacbroadinstituteorg) contains 68
THRA missense or frameshift mutations with
most
of
them
predicted
to
alter
TRa1 function
It
is
thereforelikely that several patients in the general population haveundiagnosed RTHa with milder phenotype As in RTHb it is
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the discordance between the clinical and the laboratory datathat
should
stand
out
for
the
clinician
The
identification
ofpatients with authenticated abnormalities of the
THRA gene
is
essential
for
improving
the
definition
of
the
clinical
spectrumof RTHa and more generally of all RTH and syndromes of
reduced sensitivity to thyroid hormones This improved pheno-typic definition will enable genotypendashphenotype correlations tobe
formulated
and
perhaps
the
development
of
therapeuticguidelines
The
reported
cases
show
that
the
administrationof TH in patients with RTHa does not improve all the symptomsprobably
because
the
therapeutic
management
occurs
too
latefor certain abnormalities that have already become definitivelyestablished
andor
because
the
tissue
resistance
is
too
severeThe extreme dependence for TH during the brain development isa
clear
example
of
the
need
for
early
treatment
The
significance
of this seems to depend partially on the nature of the underlyinggenetic
abnormality
The
different
murine
models
with
diversegenetic abnormalities may thus be valuable tools for testing thetherapeutic
approaches
Assuming
that
the
resistance
is
toosevere to be managed by hormonal treatment identification
of the major role in animals of the interaction of mutated TRa1with corepressors such as NCoR [48] was crucial Indeed it ledto
the
demonstration
of
the
partial
reversal
of
the
abnormalTHRA
gene
phenotype
through
the
coexpression
of
a
mutantNCoR unable to interact with the TRs [49] and through theadministration
of
an
inhibitor
of
the
corepressors-associatedhistone deacetylase activity [50]
Disclosure of interest the authors declare that they have no conflicts ofinterest concerning this article
References[1] Dumitrescu AM Refetoff S The syndromes
of reduced sensitivity to thyroid hormoneBiochim Biophys Acta 201318303987ndash 4003
[2] Refetoff S DeWind LT
DeGroot LJ Familialsyndrome combining deaf-mutism stuppledepiphyses goiter and abnormally high PBIpossible target organ refractoriness to thyroidhormone J Clin Endocrinol Metab196727279ndash 94
[3] Sakurai A TakedaK Ain K Ceccarelli P NakaiA Seino S et al Generalized resistance tothyroid hormone associated with a mutationin the ligand-binding domain of the humanthyroid hormone receptor beta Proc Nat l
Acad Sci U S A 1989868977ndash 81
[4] Vlaeminck-Guillem V Margotat A Torresani J DHerbomez M Decoulx M Wemeau JLResistance to thyroid hormone in a familywith no TRbeta gene anomaly pathogenichypotheses Ann Endocrinol (Paris)200061149ndash 94
[5] Weiss RE
Hayashi Y
Nagaya T
Petty KJMurata Y Tunca H et al Dominant inheri-tance of resistance to thyroid hormone notlinked to defects in the thyroid hormonereceptor alpha or beta genes may be dueto a defective cofactor J Clin EndocrinolMetab1996814196ndash 203
[6] Pohlenz J Weiss RE
Macchia PE Pannain SLau IT Ho H et al Five new families with
resistance to thyroid hormone not caused bymutations in the thyroid hormone receptorbeta gene J Clin Endocrinol Metab1999843919ndash 28
[7] DumitrescuAM Liao XH Abdullah MS Lado-Abeal J Majed FA Moeller LC et al Muta-tions in SECISBP2 result in abnormal thyroidhormone metabolism Nat Genet2005371247ndash 52
[8] Dumitrescu AM Liao XH Best TB Brock-mann K Refetoff S A novel syndromecombining thyroid and neurological
abnormalities is associated with mutationsin a monocarboxylate transporter gene Am J Hum Genet 200474168ndash 75
[9] Friesema EC Grueters A
Biebermann HKrude H von Moers A Reeser M et alAssociation between mutations in a thyroidhormone transporter and
severe X-linked psy-chomotor retardation Lancet 20043641435ndash 7
[10] Refetoff S Bassett JH
Beck-Peccoz P Bernal JBrent G Chatterjee K et al Classificationandproposednomenclaturefor inheriteddefects ofthyroid hormone action cell transport andmetabolism Eur Thyroid J 201437ndash 9
[11] Vlaeminck-Guillem V Wemeau JL
Physiolo-gie et physiopathologie des reacutecepteurs thyr-oiumldiens lapport des modegraveles murins AnnEndocrinol (Paris) 200061440ndash 51
[12] Wikstrom L Johansson C Salto C Barlow CCampos Barros A Baas F et al Abnormalheart rate and body temperature in micelacking thyroid hormone receptor alpha 1EMBO J 199817455ndash 61
[13] Kaneshige M Suzuki H Kaneshige K Cheng J Wimbrow H Barlow C et al A targeteddominant negative mutation of the thyroidhormone alpha 1 receptor causes increasedmortality infertility and dwarfism in miceProc Natl Acad Sci U S A 20019815095ndash 100
[14] Bochukova E Schoenmakers N Agostini M
Schoenmakers E RajanayagamO Keogh JMet al A mutation in the thyroid hormonereceptor alpha gene N Engl J Med2012366243ndash 9
[15] van Mullem A van Heerebeek R Chrysis DVisser E Medici M Andrikoula M et alClinical phenotype and mutant TRalpha1 NEngl J Med 20123661451ndash 3
[16] Moran C
Schoenmakers N Agostini MSchoenmakers E Offiah A
Kydd
A et alAn adult female with resistance to thyroidhormone mediated by defective thyroid
hormone receptor alpha J Cl in EndocrinolMetab 2013984254ndash 61
[17] Moran C Agostini M Visser WE Schoen-makers E SchoenmakersN Offiah AC etalResistance to thyroid hormone caused by amutation in thyroid hormone receptor (TR)alpha1 and
TRalpha2 clinical biochemicaland genetic analyses
of three
related patientsLancet Diabet Endocrinol 20142619ndash 26
[18] van Mullem AA Chrysis D Eythimiadou AChroni E Tsatsoulis A de Rijke YB et alClinical phenotype of a new type of thyroidhormone resistance caused by a mutation ofthe TRalpha1 receptor consequences of LT4
treatment J Clin Endocrinol Metab2013983029ndash 38
[19] Yuen RK Thiruvahindrapuram B Merico DWalker S Tammimies K Hoang N et alWhole-genome sequencing of quartetfamilies with autism spectrum disorder NatMed 201521185ndash 91
[20] Tylki-Szymanska A Acuna-Hidalgo R Kra- jewska-Walasek M Lecka-Ambroziak ASteehouwer M Gi lissen C et al Thyroidhormone resistance syndrome due to muta-tions in the thyroid hormone receptor alphagene (THRA) J Med Genet 201552312ndash 6
[21] Espiard S Savagner F
Flamant F
Vlaeminck-Guillem V Guyot R Munier M
et al A novelmutation in THRA gene associated with an
atypical phenotype of resistance to thyroidhormone J Clin Endocrinol Metab 2015 jc20151120
[22] Faivre L Cormier-Daire V GenevieveD PintoG Goulet O
Munnich A
et al A novelsyndrome with dwarfism poorly muscledbuild absent clavicles humeroradial fusionslender bones oligodactyly and micro-gnathia Clin Dysmorphol 200110181ndash 4
[23] Mundlos S Cleidocranial dysplasia clinicaland molecular genetics J Med Genet199936177ndash 82
TRa receptor mutations extend the spectrum of syndromes of reduced sensitivity tothyroid hormone ENDOCRINOLOGIE
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[24] Mundlos S Otto F
Mundlos C Mulliken JBAylsworth AS Albright S et a l Mutat ionsinvolving the transcription factor CBFA1
causecleidocranial dysplasia Cell 199789773ndash 9
[25] Margotat A
Sarkissian G Malezet-Desmou-lins C Peyrol N Vlaeminck Guillem V
Wemeau JL
et al Ident if ication of eightnew mutations in the c-erbAB gene ofpatients with resistance to thyroid hormoneAnn Endocrinol 200162220ndash 5
[26] Adams M Matthews C Coll ingwood TNToneY
Beck-Peccoz P ChatterjeeKK Geneticanalysis of 29 kindreds with generalized andpituitary resistance to thyroid hormone Iden-tification of thirteen novel mutations in thethyroid hormone receptor beta gene J ClinInvest 199494506ndash 15
[27] Groenhout EG Dorin RI Generalized thyroidhormone resistance due to a deletion of thecarboxy terminus of the c-erbA beta receptorMol Cell Endocrinol 19949981ndash 8
[28] Wu SY CohenRN SimsekE Senses DA Yar
NE Grasberger H et al A novel thyroidhormone receptor-beta mutation that failsto bind nuclear receptor corepressor in apatient as an apparent cause of severe pre-dominantly pituitary resistance to thyroid hor-mone J Clin Endocrinol Metab 2006911887ndash 95
[29] Tinnikov A Nordstrom K Thoren P Kindblom JM Malin S Rozell B et al Retardation ofpost-natal development caused by a nega-tively acting thyroid hormone receptoralpha1 EMBO J 2002215079ndash 87
[30] Parrilla R
Mixson AJ McPherson JA
McClas-key JH Weintraub BD Characterization ofseven novel mutations of the c-erbA betagene in unrelated kindreds with generalizedthyroidhormone resistance Evidence for twohot spot regions of the l igand bindingdomain J Clin Invest 1991882123ndash 30
[31] Quignodon L VincentS Winter H Samarut JFlamant F A point mutation in the
activationfunction2 domainof thyroidhormonereceptoralpha1 expressed after CRE-mediated recom-bination partially recapitulates hypothyroid-ism Mol Endocrinol 2007212350ndash 60
[32] Liu YY
Schultz JJ
Brent GA A thyroidhormone receptor alpha gene mutation
(P398H) is associated with visceral adiposityand impaired catecholamine-stimulated lipo-lysis in mice J Biol Chem 200327838913ndash 20
[33] OShea PJ Bassett JH ChengSY Williams GRCharacterization of skeletal phenotypes ofTRalpha1 and TRbeta mutant mice implica-
tions for tissue thyroid status and T3 targetgene expression Nucl Recept Signal 20064e011
[34] OShea PJ Bassett JH Sriskantharajah S YingH Cheng SY Williams GR Contrasting ske-leta l phenotypes in mice with an identicalmutation targeted to thyroid hormone recep-tor alpha1 or beta Mol Endocrinol2005193045ndash 59
[35] Desjardin C
Charles C
Benoist-Lasselin CRiviere J Gilles M Chassande O et alChondrocytes play a major role in the stimu-lation of bone growth by thyroid hormoneEndocrinology 20141553123ndash 35
[36] Venero C Guadano-Ferraz A Herrero AINordstrom K Manzano J de Escobar GM
et al Anxiety memory impairmentand loco-motor dysfunction caused by a mutant thyr-oid hormone receptor alpha1 can beameliorated by T3 treatment Genes Dev2005192152ndash 63
[37] Pilhatsch M
Winter C
Nordstrom K Venn-strom B Bauer M
Juckel G Increaseddepressive behaviour in mice harboring themutant thyroid hormone receptor alpha 1Behav Brain Res 2010214187ndash 92
[38] Kapoor R
van Hogerlinden M
Wallis KGhosh H Nordstrom K Vennstrom Bet al Unliganded thyroid hormone receptoralpha1 impairs adult hippocampal neurogen-esis FASEB J 2010244793ndash 805
[39] Bassett JH Boyde A Zikmund T Evans HCroucher PI
Zhu X
et al
Thyroid hormonereceptor alpha mutation causes a severe
andthyroxine-resistant skeletaldysplasiain femalemice Endocrinology 20141553699ndash 712
[40] Mittag J Davis B Vujovic M Arner AVennstromB Adaptations of theautonomousnervous system controlling heart rate areimpairedby amutant thyroid hormone recep-tor-alpha1 Endocrinology 20101512388ndash 95
[41] Tavi P Sjogren M Lunde PK Zhang SJAbbate F
Vennstrom B et al Impaired
Ca2+ handling and contraction in cardiomyo-cytes from mice with a dominant negativethyroid hormone receptor alpha1 J Mol CellCardiol 200538655ndash 63
[42] Mittag J Lyons DJ Sall strom J Vujovic MDudazy-Gralla S Warner A
et al Thyroid
hormone is required for hypothalamic neu-rons regulating cardiovascular functions J ClinInvest 2013123509ndash 16
[43] Warner A RahmanA Solsjo P Gottschling KDavis B Vennstrom B et al Inappropriateheatdissipation ignitesbrown fat thermogen-esis in mice with a mutant thyroid hormonereceptor alpha1 Proc Natl Acad Sci U S A201311016241ndash 46
[44] SjogrenM AlkemadeA
MittagJ
NordstromK KatzA Rozell B etal Hypermetabolisminmice caused by the central action of an unli-ganded thyroid hormone receptor alpha1EMBO J 2007264535ndash 45
[45] Ying H Araki O Furuya F Kato Y Cheng SYImpaired adipogenesis caused by a mutated
thyroid hormone alpha1 receptor Mol CellBiol 2007272359ndash 71
[46] Araki O
Ying H Zhu XG Willingham MCChengSY Distinct dysregulationof lipid meta-bolismbyunligandedthyroid hormone recep-tor isoforms Mol Endocrinol 200923308ndash 15
[47] Liu YY
Heymann RS Moatamed F
Schultz JJSobel D Brent GA A mutant thyroid hor-mone receptor alphaantagonizesperoxisomeproliferator-activated receptor alpha signalingin vivo and impairs fatty acid oxidation Endo-crinology 20071481206ndash 17
[48] Fozzatt i L Lu C
Kim DW Cheng SY Differ-ential recruitment of nuclear coregulatorsdirects the isoform-dependent action ofmutant thyroid hormonereceptorsMol Endo-crinol 201125908
ndash 21
[49] Fozzatti
L Kim
DW
ParkJW Willingham
MCHollenberg AN Cheng SY Nuclear receptorcorepresso r (NCOR1) regulates in vivoactions ofa mutated
thyroid
hormone recep-tor alpha Proc Natl
Acad
Sci U S A20131107850ndash 5
[50] Kim DW ParkJW
Willingham MC Cheng SYA histone deacetylase inhibitor improveshypothyroidism caused by a TRalpha1mutant Hum Mol Genet 2014232651ndash 64
V Vlaeminck-Guillem S Espiard F Flamant J-LWeacutemeau
tome 44 gt n811
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7252019 Thyroid Receptors
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Figure 2
The
main
isoforms
produced
by
the
THRA
gene
and
the
mutations
described
in
the
a
form
of
resistance
to
thyroid
hormonesIsoform TRa1 isa functional receptor capable of binding DNA and T3 and influencingunder thecontrolof thelatter theexpression of target genes Isoform TRa2
is incapable of
binding thehormoneand behaves like a weak dominant negative inhibitor of the T3 functionalreceptorsFor now themutations found in RTHa rein the T3 binding domain (E)
while
thehinge domain(D) theDNA-binding domain (C)and theN -terminus transactivation domain (AB) arespared Themutationsconcern the commonsequence of thetwo
isoforms TRa1andTRa2 oronlyaffectthe C -terminussequence of TRa1 (numbering in410 amino acids ofthe TRa1 receptor) Thepoint mutations arerepresentedby a star and
the
frameshift mutations by a star at the level of the first mutated amino acid fol lowed by a blue box representing the modified sequence
The four mutations introduced in the THRA gene to try to generate murine models of the a form of resistance to thyroid hormones are also indicated in italic font (R384C
P394fs406X P398H and L400R) The numbering for the murine isoform TRa1
is the same as for the human isoform
TRa receptor mutations extend the spectrum of syndromes of reduced sensitivity tothyroid hormone ENDOCRINOLOGIE
tome 44 gt n811 gt novembre2015 1 1 0 9
L i t e r a t u r e r e v i e w
7252019 Thyroid Receptors
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phenotype by profoundly affecting TR function through totalinability
to
interact
with
coactivatorsThe genotypendashphenotype correlations may in fact need to beinvestigatedin
animal
modelsMicewith
complete
inactivationof the THRA andor
THRB genes have been reported [11] but
may not represent the most relevant models as the absence ofa receptor does nothave the same consequences as the expres-sion
of
an
abnormal receptor
The comparison
is
more
logical inanimal
models
with
an
artificially
introduced
mutation For theTHRA
gene thereare fourdifferentmodels available that are allbased
on
a
mutation
of
the hormone-binding domain in
onlythe TRa1 receptor (1047297 gure 2 no model with mutation affectingTRa1
and TRa2)
One model
introduced
in
TRa1 the PV
muta-tion [13] which was identified in a patientwith RTHb (insertionof
several
nucleotides
with
modification of
the reading
frame)[30]
while
the others
introduce
point
mutations
R384C
[29](corresponding exactly to a
THRA mutation in a patient with
RTHa
[19])
L400R
[31]
and P398H
[32] These models
providephenotypic data that are complementary to those reported inhuman cases The growth retardation with impairment in ossi-fication is consistent in all animals [132931ndash34] The role ofTRa1
in
the development
of
chondrocytes
is probably a
deter-mining factor
as
the
elective introduction
of
the
L400R
muta-tion in the chondrocytes is sufficient to induce the phenotype[35]
The severity
of
the bone phenotype however
is
variabledepending on the models The bone phenotype of the R384Cmutation for instance was observed in young mice and dis-appeared in
the adultmice
[29]
In humans this
mutationwasreported in
a
girl though
it
is
only
known that
she
was
a
carrierof a familial form of autism without other information on herphenotype It is interesting to observe that the R384C mice hadsignificant psychomotor
disorders
with
anxiety memoryimpairment and depression (which are possible even fre-quent manifestations of autism) [3637] Cerebellar ataxiawas
also
observed
in
another
model
[31]
which
is
somewhatsimilar to the clumsiness and awkwardness described in thegait or the handling of objects in several patients with RTHa[141617] In animals these psychoneuromotor disorders arerelated
to impairment
of
neurogenesis
in
the hippocampus(lack of certain GABAergic interneurons) [38] and diminishpartially with levothyroxine [3638] This reduction on treat-ment
is not
observed
for the
bone
phenotype [39] as
was
also
reported in
humans Another
common
point of
the animalmodels
with
TRa1 mutations
is the
near-normality
of
TH
serumlevels On the other hand TSH has been found to be high inseveral
models
[1332]
as
opposed to its usual observed nor-mality in patients with RTHa (high-normal values in one case[16]) The T4T3 ratio and the reverse T3 (rT3) found to be lowin
patients with
RTHa
are
considered
an
indication of
theperipheral metabolism of TH Interestingly high levels of type1
deiodinase
(responsible for the conversion
of
T4
into
T3 andfor the clearance of rT3)have been measured in the liver of one
of the murine models [13] Normal levels were however
detected
in
another [31]Investigations of murine models found bradycardia [293132]which
was
rather
mild
but
accompanied
by
inadaptation
tostress [40] Bradycardia was reported in patients with RTHa
[141617] but the rare functional heart explorations that weredone did not demonstrate serious abnormalities [16] Bradycar-dia
is
probably
the
result
of
the
direct
effect
of
TH
on
themyocardium
(known
target
tissue
of
TH
expressing
ratherTRa1) abnormalities of calcium flux and contractility wereobserved
in
one
model
[41] However
there
is
probably
anothermechanism involved namely deregulation of the autonomicnervous
system
due
to
abnormal
brain
development
[4042]The same mechanism (lack of cerebral control on the autonomicnervous
system)
has
been
suggested
as
an
explanation
forthermogenesis
abnormalities
These
abnormalities
have
notbeen actually reported (not explored) in patients with RTHa
A
reduction
in
body
temperature
andor
a
cold
intolerance
wasdescribed in two murine models [3132] Dysfunction of thebrown fat is suspected related to deregulation of the autonomicnervous system caused by abnormal brain development [38]Increased
vasodilatation
again
related
to
the
autonomic
ner-vous
system
was
supposedly
also
observed
in
one
of
the
mo-dels with abnormal thermogenesis [43]One
patient
with
RTHa
had
weight
loss
(occurring
in
childhoodand continuing in adulthood) [21] while the other patients hadnormal or increased weight [15ndash18] One murine model exhib-ited
overweight
(without
increased
food
intake)
hepatic
stea-tosis
and
insulin
resistance
[32] but
a
controversy
exists
aboutthe real responsibility of THRA mutation Two others models hadhyperphagia without weight gain resistance to tube-feedingmild
adiposity
due
to
impairment
of
adipogenesis
and
low
liverconcentrations of lipids [44ndash46] The same mechanism aninteraction with PPARg has been suggested in both of thesecontrary
situations
[4547]
ConclusionsTowards the end of the 1980s the first descriptions of abnor-malities of the
THRB gene in patients with RTHb generated a
very
large
number
of
questions
about
the
possibility
of
muta-tions
in
the
THRA
gene
Answers
have
arrived
more
than
20
yearslater with the description of clinical phenotypes that are quite
particular
abnormalities
suggestive
of
mild
untreated
congeni-tal hypothyroidism in conjunction with thyroid function teststhat are more or less normal and therefore discordant For themoment
suggestive
symptoms
are
short
stature
hypothyroid-ism-like
facial
shape
and
low
T4T3
ratio
It
is
worthy
to
notethat
the
whole
exome
database
(httpexacbroadinstituteorg) contains 68
THRA missense or frameshift mutations with
most
of
them
predicted
to
alter
TRa1 function
It
is
thereforelikely that several patients in the general population haveundiagnosed RTHa with milder phenotype As in RTHb it is
V Vlaeminck-Guillem S Espiard F Flamant J-LWeacutemeau
tome 44 gt n811
gt novembre 2015 1 1 1 0
L i t e r a t u r e r e v i e w
7252019 Thyroid Receptors
httpslidepdfcomreaderfullthyroid-receptors 910
the discordance between the clinical and the laboratory datathat
should
stand
out
for
the
clinician
The
identification
ofpatients with authenticated abnormalities of the
THRA gene
is
essential
for
improving
the
definition
of
the
clinical
spectrumof RTHa and more generally of all RTH and syndromes of
reduced sensitivity to thyroid hormones This improved pheno-typic definition will enable genotypendashphenotype correlations tobe
formulated
and
perhaps
the
development
of
therapeuticguidelines
The
reported
cases
show
that
the
administrationof TH in patients with RTHa does not improve all the symptomsprobably
because
the
therapeutic
management
occurs
too
latefor certain abnormalities that have already become definitivelyestablished
andor
because
the
tissue
resistance
is
too
severeThe extreme dependence for TH during the brain development isa
clear
example
of
the
need
for
early
treatment
The
significance
of this seems to depend partially on the nature of the underlyinggenetic
abnormality
The
different
murine
models
with
diversegenetic abnormalities may thus be valuable tools for testing thetherapeutic
approaches
Assuming
that
the
resistance
is
toosevere to be managed by hormonal treatment identification
of the major role in animals of the interaction of mutated TRa1with corepressors such as NCoR [48] was crucial Indeed it ledto
the
demonstration
of
the
partial
reversal
of
the
abnormalTHRA
gene
phenotype
through
the
coexpression
of
a
mutantNCoR unable to interact with the TRs [49] and through theadministration
of
an
inhibitor
of
the
corepressors-associatedhistone deacetylase activity [50]
Disclosure of interest the authors declare that they have no conflicts ofinterest concerning this article
References[1] Dumitrescu AM Refetoff S The syndromes
of reduced sensitivity to thyroid hormoneBiochim Biophys Acta 201318303987ndash 4003
[2] Refetoff S DeWind LT
DeGroot LJ Familialsyndrome combining deaf-mutism stuppledepiphyses goiter and abnormally high PBIpossible target organ refractoriness to thyroidhormone J Clin Endocrinol Metab196727279ndash 94
[3] Sakurai A TakedaK Ain K Ceccarelli P NakaiA Seino S et al Generalized resistance tothyroid hormone associated with a mutationin the ligand-binding domain of the humanthyroid hormone receptor beta Proc Nat l
Acad Sci U S A 1989868977ndash 81
[4] Vlaeminck-Guillem V Margotat A Torresani J DHerbomez M Decoulx M Wemeau JLResistance to thyroid hormone in a familywith no TRbeta gene anomaly pathogenichypotheses Ann Endocrinol (Paris)200061149ndash 94
[5] Weiss RE
Hayashi Y
Nagaya T
Petty KJMurata Y Tunca H et al Dominant inheri-tance of resistance to thyroid hormone notlinked to defects in the thyroid hormonereceptor alpha or beta genes may be dueto a defective cofactor J Clin EndocrinolMetab1996814196ndash 203
[6] Pohlenz J Weiss RE
Macchia PE Pannain SLau IT Ho H et al Five new families with
resistance to thyroid hormone not caused bymutations in the thyroid hormone receptorbeta gene J Clin Endocrinol Metab1999843919ndash 28
[7] DumitrescuAM Liao XH Abdullah MS Lado-Abeal J Majed FA Moeller LC et al Muta-tions in SECISBP2 result in abnormal thyroidhormone metabolism Nat Genet2005371247ndash 52
[8] Dumitrescu AM Liao XH Best TB Brock-mann K Refetoff S A novel syndromecombining thyroid and neurological
abnormalities is associated with mutationsin a monocarboxylate transporter gene Am J Hum Genet 200474168ndash 75
[9] Friesema EC Grueters A
Biebermann HKrude H von Moers A Reeser M et alAssociation between mutations in a thyroidhormone transporter and
severe X-linked psy-chomotor retardation Lancet 20043641435ndash 7
[10] Refetoff S Bassett JH
Beck-Peccoz P Bernal JBrent G Chatterjee K et al Classificationandproposednomenclaturefor inheriteddefects ofthyroid hormone action cell transport andmetabolism Eur Thyroid J 201437ndash 9
[11] Vlaeminck-Guillem V Wemeau JL
Physiolo-gie et physiopathologie des reacutecepteurs thyr-oiumldiens lapport des modegraveles murins AnnEndocrinol (Paris) 200061440ndash 51
[12] Wikstrom L Johansson C Salto C Barlow CCampos Barros A Baas F et al Abnormalheart rate and body temperature in micelacking thyroid hormone receptor alpha 1EMBO J 199817455ndash 61
[13] Kaneshige M Suzuki H Kaneshige K Cheng J Wimbrow H Barlow C et al A targeteddominant negative mutation of the thyroidhormone alpha 1 receptor causes increasedmortality infertility and dwarfism in miceProc Natl Acad Sci U S A 20019815095ndash 100
[14] Bochukova E Schoenmakers N Agostini M
Schoenmakers E RajanayagamO Keogh JMet al A mutation in the thyroid hormonereceptor alpha gene N Engl J Med2012366243ndash 9
[15] van Mullem A van Heerebeek R Chrysis DVisser E Medici M Andrikoula M et alClinical phenotype and mutant TRalpha1 NEngl J Med 20123661451ndash 3
[16] Moran C
Schoenmakers N Agostini MSchoenmakers E Offiah A
Kydd
A et alAn adult female with resistance to thyroidhormone mediated by defective thyroid
hormone receptor alpha J Cl in EndocrinolMetab 2013984254ndash 61
[17] Moran C Agostini M Visser WE Schoen-makers E SchoenmakersN Offiah AC etalResistance to thyroid hormone caused by amutation in thyroid hormone receptor (TR)alpha1 and
TRalpha2 clinical biochemicaland genetic analyses
of three
related patientsLancet Diabet Endocrinol 20142619ndash 26
[18] van Mullem AA Chrysis D Eythimiadou AChroni E Tsatsoulis A de Rijke YB et alClinical phenotype of a new type of thyroidhormone resistance caused by a mutation ofthe TRalpha1 receptor consequences of LT4
treatment J Clin Endocrinol Metab2013983029ndash 38
[19] Yuen RK Thiruvahindrapuram B Merico DWalker S Tammimies K Hoang N et alWhole-genome sequencing of quartetfamilies with autism spectrum disorder NatMed 201521185ndash 91
[20] Tylki-Szymanska A Acuna-Hidalgo R Kra- jewska-Walasek M Lecka-Ambroziak ASteehouwer M Gi lissen C et al Thyroidhormone resistance syndrome due to muta-tions in the thyroid hormone receptor alphagene (THRA) J Med Genet 201552312ndash 6
[21] Espiard S Savagner F
Flamant F
Vlaeminck-Guillem V Guyot R Munier M
et al A novelmutation in THRA gene associated with an
atypical phenotype of resistance to thyroidhormone J Clin Endocrinol Metab 2015 jc20151120
[22] Faivre L Cormier-Daire V GenevieveD PintoG Goulet O
Munnich A
et al A novelsyndrome with dwarfism poorly muscledbuild absent clavicles humeroradial fusionslender bones oligodactyly and micro-gnathia Clin Dysmorphol 200110181ndash 4
[23] Mundlos S Cleidocranial dysplasia clinicaland molecular genetics J Med Genet199936177ndash 82
TRa receptor mutations extend the spectrum of syndromes of reduced sensitivity tothyroid hormone ENDOCRINOLOGIE
tome 44 gt n811 gt novembre2015 1 1 1 1
L i t e r a t u r e r e v i e w
7252019 Thyroid Receptors
httpslidepdfcomreaderfullthyroid-receptors 1010
[24] Mundlos S Otto F
Mundlos C Mulliken JBAylsworth AS Albright S et a l Mutat ionsinvolving the transcription factor CBFA1
causecleidocranial dysplasia Cell 199789773ndash 9
[25] Margotat A
Sarkissian G Malezet-Desmou-lins C Peyrol N Vlaeminck Guillem V
Wemeau JL
et al Ident if ication of eightnew mutations in the c-erbAB gene ofpatients with resistance to thyroid hormoneAnn Endocrinol 200162220ndash 5
[26] Adams M Matthews C Coll ingwood TNToneY
Beck-Peccoz P ChatterjeeKK Geneticanalysis of 29 kindreds with generalized andpituitary resistance to thyroid hormone Iden-tification of thirteen novel mutations in thethyroid hormone receptor beta gene J ClinInvest 199494506ndash 15
[27] Groenhout EG Dorin RI Generalized thyroidhormone resistance due to a deletion of thecarboxy terminus of the c-erbA beta receptorMol Cell Endocrinol 19949981ndash 8
[28] Wu SY CohenRN SimsekE Senses DA Yar
NE Grasberger H et al A novel thyroidhormone receptor-beta mutation that failsto bind nuclear receptor corepressor in apatient as an apparent cause of severe pre-dominantly pituitary resistance to thyroid hor-mone J Clin Endocrinol Metab 2006911887ndash 95
[29] Tinnikov A Nordstrom K Thoren P Kindblom JM Malin S Rozell B et al Retardation ofpost-natal development caused by a nega-tively acting thyroid hormone receptoralpha1 EMBO J 2002215079ndash 87
[30] Parrilla R
Mixson AJ McPherson JA
McClas-key JH Weintraub BD Characterization ofseven novel mutations of the c-erbA betagene in unrelated kindreds with generalizedthyroidhormone resistance Evidence for twohot spot regions of the l igand bindingdomain J Clin Invest 1991882123ndash 30
[31] Quignodon L VincentS Winter H Samarut JFlamant F A point mutation in the
activationfunction2 domainof thyroidhormonereceptoralpha1 expressed after CRE-mediated recom-bination partially recapitulates hypothyroid-ism Mol Endocrinol 2007212350ndash 60
[32] Liu YY
Schultz JJ
Brent GA A thyroidhormone receptor alpha gene mutation
(P398H) is associated with visceral adiposityand impaired catecholamine-stimulated lipo-lysis in mice J Biol Chem 200327838913ndash 20
[33] OShea PJ Bassett JH ChengSY Williams GRCharacterization of skeletal phenotypes ofTRalpha1 and TRbeta mutant mice implica-
tions for tissue thyroid status and T3 targetgene expression Nucl Recept Signal 20064e011
[34] OShea PJ Bassett JH Sriskantharajah S YingH Cheng SY Williams GR Contrasting ske-leta l phenotypes in mice with an identicalmutation targeted to thyroid hormone recep-tor alpha1 or beta Mol Endocrinol2005193045ndash 59
[35] Desjardin C
Charles C
Benoist-Lasselin CRiviere J Gilles M Chassande O et alChondrocytes play a major role in the stimu-lation of bone growth by thyroid hormoneEndocrinology 20141553123ndash 35
[36] Venero C Guadano-Ferraz A Herrero AINordstrom K Manzano J de Escobar GM
et al Anxiety memory impairmentand loco-motor dysfunction caused by a mutant thyr-oid hormone receptor alpha1 can beameliorated by T3 treatment Genes Dev2005192152ndash 63
[37] Pilhatsch M
Winter C
Nordstrom K Venn-strom B Bauer M
Juckel G Increaseddepressive behaviour in mice harboring themutant thyroid hormone receptor alpha 1Behav Brain Res 2010214187ndash 92
[38] Kapoor R
van Hogerlinden M
Wallis KGhosh H Nordstrom K Vennstrom Bet al Unliganded thyroid hormone receptoralpha1 impairs adult hippocampal neurogen-esis FASEB J 2010244793ndash 805
[39] Bassett JH Boyde A Zikmund T Evans HCroucher PI
Zhu X
et al
Thyroid hormonereceptor alpha mutation causes a severe
andthyroxine-resistant skeletaldysplasiain femalemice Endocrinology 20141553699ndash 712
[40] Mittag J Davis B Vujovic M Arner AVennstromB Adaptations of theautonomousnervous system controlling heart rate areimpairedby amutant thyroid hormone recep-tor-alpha1 Endocrinology 20101512388ndash 95
[41] Tavi P Sjogren M Lunde PK Zhang SJAbbate F
Vennstrom B et al Impaired
Ca2+ handling and contraction in cardiomyo-cytes from mice with a dominant negativethyroid hormone receptor alpha1 J Mol CellCardiol 200538655ndash 63
[42] Mittag J Lyons DJ Sall strom J Vujovic MDudazy-Gralla S Warner A
et al Thyroid
hormone is required for hypothalamic neu-rons regulating cardiovascular functions J ClinInvest 2013123509ndash 16
[43] Warner A RahmanA Solsjo P Gottschling KDavis B Vennstrom B et al Inappropriateheatdissipation ignitesbrown fat thermogen-esis in mice with a mutant thyroid hormonereceptor alpha1 Proc Natl Acad Sci U S A201311016241ndash 46
[44] SjogrenM AlkemadeA
MittagJ
NordstromK KatzA Rozell B etal Hypermetabolisminmice caused by the central action of an unli-ganded thyroid hormone receptor alpha1EMBO J 2007264535ndash 45
[45] Ying H Araki O Furuya F Kato Y Cheng SYImpaired adipogenesis caused by a mutated
thyroid hormone alpha1 receptor Mol CellBiol 2007272359ndash 71
[46] Araki O
Ying H Zhu XG Willingham MCChengSY Distinct dysregulationof lipid meta-bolismbyunligandedthyroid hormone recep-tor isoforms Mol Endocrinol 200923308ndash 15
[47] Liu YY
Heymann RS Moatamed F
Schultz JJSobel D Brent GA A mutant thyroid hor-mone receptor alphaantagonizesperoxisomeproliferator-activated receptor alpha signalingin vivo and impairs fatty acid oxidation Endo-crinology 20071481206ndash 17
[48] Fozzatt i L Lu C
Kim DW Cheng SY Differ-ential recruitment of nuclear coregulatorsdirects the isoform-dependent action ofmutant thyroid hormonereceptorsMol Endo-crinol 201125908
ndash 21
[49] Fozzatti
L Kim
DW
ParkJW Willingham
MCHollenberg AN Cheng SY Nuclear receptorcorepresso r (NCOR1) regulates in vivoactions ofa mutated
thyroid
hormone recep-tor alpha Proc Natl
Acad
Sci U S A20131107850ndash 5
[50] Kim DW ParkJW
Willingham MC Cheng SYA histone deacetylase inhibitor improveshypothyroidism caused by a TRalpha1mutant Hum Mol Genet 2014232651ndash 64
V Vlaeminck-Guillem S Espiard F Flamant J-LWeacutemeau
tome 44 gt n811
gt novembre 2015 1 1 1 2
L i t e r a t u r e r e v i e w
7252019 Thyroid Receptors
httpslidepdfcomreaderfullthyroid-receptors 810
phenotype by profoundly affecting TR function through totalinability
to
interact
with
coactivatorsThe genotypendashphenotype correlations may in fact need to beinvestigatedin
animal
modelsMicewith
complete
inactivationof the THRA andor
THRB genes have been reported [11] but
may not represent the most relevant models as the absence ofa receptor does nothave the same consequences as the expres-sion
of
an
abnormal receptor
The comparison
is
more
logical inanimal
models
with
an
artificially
introduced
mutation For theTHRA
gene thereare fourdifferentmodels available that are allbased
on
a
mutation
of
the hormone-binding domain in
onlythe TRa1 receptor (1047297 gure 2 no model with mutation affectingTRa1
and TRa2)
One model
introduced
in
TRa1 the PV
muta-tion [13] which was identified in a patientwith RTHb (insertionof
several
nucleotides
with
modification of
the reading
frame)[30]
while
the others
introduce
point
mutations
R384C
[29](corresponding exactly to a
THRA mutation in a patient with
RTHa
[19])
L400R
[31]
and P398H
[32] These models
providephenotypic data that are complementary to those reported inhuman cases The growth retardation with impairment in ossi-fication is consistent in all animals [132931ndash34] The role ofTRa1
in
the development
of
chondrocytes
is probably a
deter-mining factor
as
the
elective introduction
of
the
L400R
muta-tion in the chondrocytes is sufficient to induce the phenotype[35]
The severity
of
the bone phenotype however
is
variabledepending on the models The bone phenotype of the R384Cmutation for instance was observed in young mice and dis-appeared in
the adultmice
[29]
In humans this
mutationwasreported in
a
girl though
it
is
only
known that
she
was
a
carrierof a familial form of autism without other information on herphenotype It is interesting to observe that the R384C mice hadsignificant psychomotor
disorders
with
anxiety memoryimpairment and depression (which are possible even fre-quent manifestations of autism) [3637] Cerebellar ataxiawas
also
observed
in
another
model
[31]
which
is
somewhatsimilar to the clumsiness and awkwardness described in thegait or the handling of objects in several patients with RTHa[141617] In animals these psychoneuromotor disorders arerelated
to impairment
of
neurogenesis
in
the hippocampus(lack of certain GABAergic interneurons) [38] and diminishpartially with levothyroxine [3638] This reduction on treat-ment
is not
observed
for the
bone
phenotype [39] as
was
also
reported in
humans Another
common
point of
the animalmodels
with
TRa1 mutations
is the
near-normality
of
TH
serumlevels On the other hand TSH has been found to be high inseveral
models
[1332]
as
opposed to its usual observed nor-mality in patients with RTHa (high-normal values in one case[16]) The T4T3 ratio and the reverse T3 (rT3) found to be lowin
patients with
RTHa
are
considered
an
indication of
theperipheral metabolism of TH Interestingly high levels of type1
deiodinase
(responsible for the conversion
of
T4
into
T3 andfor the clearance of rT3)have been measured in the liver of one
of the murine models [13] Normal levels were however
detected
in
another [31]Investigations of murine models found bradycardia [293132]which
was
rather
mild
but
accompanied
by
inadaptation
tostress [40] Bradycardia was reported in patients with RTHa
[141617] but the rare functional heart explorations that weredone did not demonstrate serious abnormalities [16] Bradycar-dia
is
probably
the
result
of
the
direct
effect
of
TH
on
themyocardium
(known
target
tissue
of
TH
expressing
ratherTRa1) abnormalities of calcium flux and contractility wereobserved
in
one
model
[41] However
there
is
probably
anothermechanism involved namely deregulation of the autonomicnervous
system
due
to
abnormal
brain
development
[4042]The same mechanism (lack of cerebral control on the autonomicnervous
system)
has
been
suggested
as
an
explanation
forthermogenesis
abnormalities
These
abnormalities
have
notbeen actually reported (not explored) in patients with RTHa
A
reduction
in
body
temperature
andor
a
cold
intolerance
wasdescribed in two murine models [3132] Dysfunction of thebrown fat is suspected related to deregulation of the autonomicnervous system caused by abnormal brain development [38]Increased
vasodilatation
again
related
to
the
autonomic
ner-vous
system
was
supposedly
also
observed
in
one
of
the
mo-dels with abnormal thermogenesis [43]One
patient
with
RTHa
had
weight
loss
(occurring
in
childhoodand continuing in adulthood) [21] while the other patients hadnormal or increased weight [15ndash18] One murine model exhib-ited
overweight
(without
increased
food
intake)
hepatic
stea-tosis
and
insulin
resistance
[32] but
a
controversy
exists
aboutthe real responsibility of THRA mutation Two others models hadhyperphagia without weight gain resistance to tube-feedingmild
adiposity
due
to
impairment
of
adipogenesis
and
low
liverconcentrations of lipids [44ndash46] The same mechanism aninteraction with PPARg has been suggested in both of thesecontrary
situations
[4547]
ConclusionsTowards the end of the 1980s the first descriptions of abnor-malities of the
THRB gene in patients with RTHb generated a
very
large
number
of
questions
about
the
possibility
of
muta-tions
in
the
THRA
gene
Answers
have
arrived
more
than
20
yearslater with the description of clinical phenotypes that are quite
particular
abnormalities
suggestive
of
mild
untreated
congeni-tal hypothyroidism in conjunction with thyroid function teststhat are more or less normal and therefore discordant For themoment
suggestive
symptoms
are
short
stature
hypothyroid-ism-like
facial
shape
and
low
T4T3
ratio
It
is
worthy
to
notethat
the
whole
exome
database
(httpexacbroadinstituteorg) contains 68
THRA missense or frameshift mutations with
most
of
them
predicted
to
alter
TRa1 function
It
is
thereforelikely that several patients in the general population haveundiagnosed RTHa with milder phenotype As in RTHb it is
V Vlaeminck-Guillem S Espiard F Flamant J-LWeacutemeau
tome 44 gt n811
gt novembre 2015 1 1 1 0
L i t e r a t u r e r e v i e w
7252019 Thyroid Receptors
httpslidepdfcomreaderfullthyroid-receptors 910
the discordance between the clinical and the laboratory datathat
should
stand
out
for
the
clinician
The
identification
ofpatients with authenticated abnormalities of the
THRA gene
is
essential
for
improving
the
definition
of
the
clinical
spectrumof RTHa and more generally of all RTH and syndromes of
reduced sensitivity to thyroid hormones This improved pheno-typic definition will enable genotypendashphenotype correlations tobe
formulated
and
perhaps
the
development
of
therapeuticguidelines
The
reported
cases
show
that
the
administrationof TH in patients with RTHa does not improve all the symptomsprobably
because
the
therapeutic
management
occurs
too
latefor certain abnormalities that have already become definitivelyestablished
andor
because
the
tissue
resistance
is
too
severeThe extreme dependence for TH during the brain development isa
clear
example
of
the
need
for
early
treatment
The
significance
of this seems to depend partially on the nature of the underlyinggenetic
abnormality
The
different
murine
models
with
diversegenetic abnormalities may thus be valuable tools for testing thetherapeutic
approaches
Assuming
that
the
resistance
is
toosevere to be managed by hormonal treatment identification
of the major role in animals of the interaction of mutated TRa1with corepressors such as NCoR [48] was crucial Indeed it ledto
the
demonstration
of
the
partial
reversal
of
the
abnormalTHRA
gene
phenotype
through
the
coexpression
of
a
mutantNCoR unable to interact with the TRs [49] and through theadministration
of
an
inhibitor
of
the
corepressors-associatedhistone deacetylase activity [50]
Disclosure of interest the authors declare that they have no conflicts ofinterest concerning this article
References[1] Dumitrescu AM Refetoff S The syndromes
of reduced sensitivity to thyroid hormoneBiochim Biophys Acta 201318303987ndash 4003
[2] Refetoff S DeWind LT
DeGroot LJ Familialsyndrome combining deaf-mutism stuppledepiphyses goiter and abnormally high PBIpossible target organ refractoriness to thyroidhormone J Clin Endocrinol Metab196727279ndash 94
[3] Sakurai A TakedaK Ain K Ceccarelli P NakaiA Seino S et al Generalized resistance tothyroid hormone associated with a mutationin the ligand-binding domain of the humanthyroid hormone receptor beta Proc Nat l
Acad Sci U S A 1989868977ndash 81
[4] Vlaeminck-Guillem V Margotat A Torresani J DHerbomez M Decoulx M Wemeau JLResistance to thyroid hormone in a familywith no TRbeta gene anomaly pathogenichypotheses Ann Endocrinol (Paris)200061149ndash 94
[5] Weiss RE
Hayashi Y
Nagaya T
Petty KJMurata Y Tunca H et al Dominant inheri-tance of resistance to thyroid hormone notlinked to defects in the thyroid hormonereceptor alpha or beta genes may be dueto a defective cofactor J Clin EndocrinolMetab1996814196ndash 203
[6] Pohlenz J Weiss RE
Macchia PE Pannain SLau IT Ho H et al Five new families with
resistance to thyroid hormone not caused bymutations in the thyroid hormone receptorbeta gene J Clin Endocrinol Metab1999843919ndash 28
[7] DumitrescuAM Liao XH Abdullah MS Lado-Abeal J Majed FA Moeller LC et al Muta-tions in SECISBP2 result in abnormal thyroidhormone metabolism Nat Genet2005371247ndash 52
[8] Dumitrescu AM Liao XH Best TB Brock-mann K Refetoff S A novel syndromecombining thyroid and neurological
abnormalities is associated with mutationsin a monocarboxylate transporter gene Am J Hum Genet 200474168ndash 75
[9] Friesema EC Grueters A
Biebermann HKrude H von Moers A Reeser M et alAssociation between mutations in a thyroidhormone transporter and
severe X-linked psy-chomotor retardation Lancet 20043641435ndash 7
[10] Refetoff S Bassett JH
Beck-Peccoz P Bernal JBrent G Chatterjee K et al Classificationandproposednomenclaturefor inheriteddefects ofthyroid hormone action cell transport andmetabolism Eur Thyroid J 201437ndash 9
[11] Vlaeminck-Guillem V Wemeau JL
Physiolo-gie et physiopathologie des reacutecepteurs thyr-oiumldiens lapport des modegraveles murins AnnEndocrinol (Paris) 200061440ndash 51
[12] Wikstrom L Johansson C Salto C Barlow CCampos Barros A Baas F et al Abnormalheart rate and body temperature in micelacking thyroid hormone receptor alpha 1EMBO J 199817455ndash 61
[13] Kaneshige M Suzuki H Kaneshige K Cheng J Wimbrow H Barlow C et al A targeteddominant negative mutation of the thyroidhormone alpha 1 receptor causes increasedmortality infertility and dwarfism in miceProc Natl Acad Sci U S A 20019815095ndash 100
[14] Bochukova E Schoenmakers N Agostini M
Schoenmakers E RajanayagamO Keogh JMet al A mutation in the thyroid hormonereceptor alpha gene N Engl J Med2012366243ndash 9
[15] van Mullem A van Heerebeek R Chrysis DVisser E Medici M Andrikoula M et alClinical phenotype and mutant TRalpha1 NEngl J Med 20123661451ndash 3
[16] Moran C
Schoenmakers N Agostini MSchoenmakers E Offiah A
Kydd
A et alAn adult female with resistance to thyroidhormone mediated by defective thyroid
hormone receptor alpha J Cl in EndocrinolMetab 2013984254ndash 61
[17] Moran C Agostini M Visser WE Schoen-makers E SchoenmakersN Offiah AC etalResistance to thyroid hormone caused by amutation in thyroid hormone receptor (TR)alpha1 and
TRalpha2 clinical biochemicaland genetic analyses
of three
related patientsLancet Diabet Endocrinol 20142619ndash 26
[18] van Mullem AA Chrysis D Eythimiadou AChroni E Tsatsoulis A de Rijke YB et alClinical phenotype of a new type of thyroidhormone resistance caused by a mutation ofthe TRalpha1 receptor consequences of LT4
treatment J Clin Endocrinol Metab2013983029ndash 38
[19] Yuen RK Thiruvahindrapuram B Merico DWalker S Tammimies K Hoang N et alWhole-genome sequencing of quartetfamilies with autism spectrum disorder NatMed 201521185ndash 91
[20] Tylki-Szymanska A Acuna-Hidalgo R Kra- jewska-Walasek M Lecka-Ambroziak ASteehouwer M Gi lissen C et al Thyroidhormone resistance syndrome due to muta-tions in the thyroid hormone receptor alphagene (THRA) J Med Genet 201552312ndash 6
[21] Espiard S Savagner F
Flamant F
Vlaeminck-Guillem V Guyot R Munier M
et al A novelmutation in THRA gene associated with an
atypical phenotype of resistance to thyroidhormone J Clin Endocrinol Metab 2015 jc20151120
[22] Faivre L Cormier-Daire V GenevieveD PintoG Goulet O
Munnich A
et al A novelsyndrome with dwarfism poorly muscledbuild absent clavicles humeroradial fusionslender bones oligodactyly and micro-gnathia Clin Dysmorphol 200110181ndash 4
[23] Mundlos S Cleidocranial dysplasia clinicaland molecular genetics J Med Genet199936177ndash 82
TRa receptor mutations extend the spectrum of syndromes of reduced sensitivity tothyroid hormone ENDOCRINOLOGIE
tome 44 gt n811 gt novembre2015 1 1 1 1
L i t e r a t u r e r e v i e w
7252019 Thyroid Receptors
httpslidepdfcomreaderfullthyroid-receptors 1010
[24] Mundlos S Otto F
Mundlos C Mulliken JBAylsworth AS Albright S et a l Mutat ionsinvolving the transcription factor CBFA1
causecleidocranial dysplasia Cell 199789773ndash 9
[25] Margotat A
Sarkissian G Malezet-Desmou-lins C Peyrol N Vlaeminck Guillem V
Wemeau JL
et al Ident if ication of eightnew mutations in the c-erbAB gene ofpatients with resistance to thyroid hormoneAnn Endocrinol 200162220ndash 5
[26] Adams M Matthews C Coll ingwood TNToneY
Beck-Peccoz P ChatterjeeKK Geneticanalysis of 29 kindreds with generalized andpituitary resistance to thyroid hormone Iden-tification of thirteen novel mutations in thethyroid hormone receptor beta gene J ClinInvest 199494506ndash 15
[27] Groenhout EG Dorin RI Generalized thyroidhormone resistance due to a deletion of thecarboxy terminus of the c-erbA beta receptorMol Cell Endocrinol 19949981ndash 8
[28] Wu SY CohenRN SimsekE Senses DA Yar
NE Grasberger H et al A novel thyroidhormone receptor-beta mutation that failsto bind nuclear receptor corepressor in apatient as an apparent cause of severe pre-dominantly pituitary resistance to thyroid hor-mone J Clin Endocrinol Metab 2006911887ndash 95
[29] Tinnikov A Nordstrom K Thoren P Kindblom JM Malin S Rozell B et al Retardation ofpost-natal development caused by a nega-tively acting thyroid hormone receptoralpha1 EMBO J 2002215079ndash 87
[30] Parrilla R
Mixson AJ McPherson JA
McClas-key JH Weintraub BD Characterization ofseven novel mutations of the c-erbA betagene in unrelated kindreds with generalizedthyroidhormone resistance Evidence for twohot spot regions of the l igand bindingdomain J Clin Invest 1991882123ndash 30
[31] Quignodon L VincentS Winter H Samarut JFlamant F A point mutation in the
activationfunction2 domainof thyroidhormonereceptoralpha1 expressed after CRE-mediated recom-bination partially recapitulates hypothyroid-ism Mol Endocrinol 2007212350ndash 60
[32] Liu YY
Schultz JJ
Brent GA A thyroidhormone receptor alpha gene mutation
(P398H) is associated with visceral adiposityand impaired catecholamine-stimulated lipo-lysis in mice J Biol Chem 200327838913ndash 20
[33] OShea PJ Bassett JH ChengSY Williams GRCharacterization of skeletal phenotypes ofTRalpha1 and TRbeta mutant mice implica-
tions for tissue thyroid status and T3 targetgene expression Nucl Recept Signal 20064e011
[34] OShea PJ Bassett JH Sriskantharajah S YingH Cheng SY Williams GR Contrasting ske-leta l phenotypes in mice with an identicalmutation targeted to thyroid hormone recep-tor alpha1 or beta Mol Endocrinol2005193045ndash 59
[35] Desjardin C
Charles C
Benoist-Lasselin CRiviere J Gilles M Chassande O et alChondrocytes play a major role in the stimu-lation of bone growth by thyroid hormoneEndocrinology 20141553123ndash 35
[36] Venero C Guadano-Ferraz A Herrero AINordstrom K Manzano J de Escobar GM
et al Anxiety memory impairmentand loco-motor dysfunction caused by a mutant thyr-oid hormone receptor alpha1 can beameliorated by T3 treatment Genes Dev2005192152ndash 63
[37] Pilhatsch M
Winter C
Nordstrom K Venn-strom B Bauer M
Juckel G Increaseddepressive behaviour in mice harboring themutant thyroid hormone receptor alpha 1Behav Brain Res 2010214187ndash 92
[38] Kapoor R
van Hogerlinden M
Wallis KGhosh H Nordstrom K Vennstrom Bet al Unliganded thyroid hormone receptoralpha1 impairs adult hippocampal neurogen-esis FASEB J 2010244793ndash 805
[39] Bassett JH Boyde A Zikmund T Evans HCroucher PI
Zhu X
et al
Thyroid hormonereceptor alpha mutation causes a severe
andthyroxine-resistant skeletaldysplasiain femalemice Endocrinology 20141553699ndash 712
[40] Mittag J Davis B Vujovic M Arner AVennstromB Adaptations of theautonomousnervous system controlling heart rate areimpairedby amutant thyroid hormone recep-tor-alpha1 Endocrinology 20101512388ndash 95
[41] Tavi P Sjogren M Lunde PK Zhang SJAbbate F
Vennstrom B et al Impaired
Ca2+ handling and contraction in cardiomyo-cytes from mice with a dominant negativethyroid hormone receptor alpha1 J Mol CellCardiol 200538655ndash 63
[42] Mittag J Lyons DJ Sall strom J Vujovic MDudazy-Gralla S Warner A
et al Thyroid
hormone is required for hypothalamic neu-rons regulating cardiovascular functions J ClinInvest 2013123509ndash 16
[43] Warner A RahmanA Solsjo P Gottschling KDavis B Vennstrom B et al Inappropriateheatdissipation ignitesbrown fat thermogen-esis in mice with a mutant thyroid hormonereceptor alpha1 Proc Natl Acad Sci U S A201311016241ndash 46
[44] SjogrenM AlkemadeA
MittagJ
NordstromK KatzA Rozell B etal Hypermetabolisminmice caused by the central action of an unli-ganded thyroid hormone receptor alpha1EMBO J 2007264535ndash 45
[45] Ying H Araki O Furuya F Kato Y Cheng SYImpaired adipogenesis caused by a mutated
thyroid hormone alpha1 receptor Mol CellBiol 2007272359ndash 71
[46] Araki O
Ying H Zhu XG Willingham MCChengSY Distinct dysregulationof lipid meta-bolismbyunligandedthyroid hormone recep-tor isoforms Mol Endocrinol 200923308ndash 15
[47] Liu YY
Heymann RS Moatamed F
Schultz JJSobel D Brent GA A mutant thyroid hor-mone receptor alphaantagonizesperoxisomeproliferator-activated receptor alpha signalingin vivo and impairs fatty acid oxidation Endo-crinology 20071481206ndash 17
[48] Fozzatt i L Lu C
Kim DW Cheng SY Differ-ential recruitment of nuclear coregulatorsdirects the isoform-dependent action ofmutant thyroid hormonereceptorsMol Endo-crinol 201125908
ndash 21
[49] Fozzatti
L Kim
DW
ParkJW Willingham
MCHollenberg AN Cheng SY Nuclear receptorcorepresso r (NCOR1) regulates in vivoactions ofa mutated
thyroid
hormone recep-tor alpha Proc Natl
Acad
Sci U S A20131107850ndash 5
[50] Kim DW ParkJW
Willingham MC Cheng SYA histone deacetylase inhibitor improveshypothyroidism caused by a TRalpha1mutant Hum Mol Genet 2014232651ndash 64
V Vlaeminck-Guillem S Espiard F Flamant J-LWeacutemeau
tome 44 gt n811
gt novembre 2015 1 1 1 2
L i t e r a t u r e r e v i e w
7252019 Thyroid Receptors
httpslidepdfcomreaderfullthyroid-receptors 910
the discordance between the clinical and the laboratory datathat
should
stand
out
for
the
clinician
The
identification
ofpatients with authenticated abnormalities of the
THRA gene
is
essential
for
improving
the
definition
of
the
clinical
spectrumof RTHa and more generally of all RTH and syndromes of
reduced sensitivity to thyroid hormones This improved pheno-typic definition will enable genotypendashphenotype correlations tobe
formulated
and
perhaps
the
development
of
therapeuticguidelines
The
reported
cases
show
that
the
administrationof TH in patients with RTHa does not improve all the symptomsprobably
because
the
therapeutic
management
occurs
too
latefor certain abnormalities that have already become definitivelyestablished
andor
because
the
tissue
resistance
is
too
severeThe extreme dependence for TH during the brain development isa
clear
example
of
the
need
for
early
treatment
The
significance
of this seems to depend partially on the nature of the underlyinggenetic
abnormality
The
different
murine
models
with
diversegenetic abnormalities may thus be valuable tools for testing thetherapeutic
approaches
Assuming
that
the
resistance
is
toosevere to be managed by hormonal treatment identification
of the major role in animals of the interaction of mutated TRa1with corepressors such as NCoR [48] was crucial Indeed it ledto
the
demonstration
of
the
partial
reversal
of
the
abnormalTHRA
gene
phenotype
through
the
coexpression
of
a
mutantNCoR unable to interact with the TRs [49] and through theadministration
of
an
inhibitor
of
the
corepressors-associatedhistone deacetylase activity [50]
Disclosure of interest the authors declare that they have no conflicts ofinterest concerning this article
References[1] Dumitrescu AM Refetoff S The syndromes
of reduced sensitivity to thyroid hormoneBiochim Biophys Acta 201318303987ndash 4003
[2] Refetoff S DeWind LT
DeGroot LJ Familialsyndrome combining deaf-mutism stuppledepiphyses goiter and abnormally high PBIpossible target organ refractoriness to thyroidhormone J Clin Endocrinol Metab196727279ndash 94
[3] Sakurai A TakedaK Ain K Ceccarelli P NakaiA Seino S et al Generalized resistance tothyroid hormone associated with a mutationin the ligand-binding domain of the humanthyroid hormone receptor beta Proc Nat l
Acad Sci U S A 1989868977ndash 81
[4] Vlaeminck-Guillem V Margotat A Torresani J DHerbomez M Decoulx M Wemeau JLResistance to thyroid hormone in a familywith no TRbeta gene anomaly pathogenichypotheses Ann Endocrinol (Paris)200061149ndash 94
[5] Weiss RE
Hayashi Y
Nagaya T
Petty KJMurata Y Tunca H et al Dominant inheri-tance of resistance to thyroid hormone notlinked to defects in the thyroid hormonereceptor alpha or beta genes may be dueto a defective cofactor J Clin EndocrinolMetab1996814196ndash 203
[6] Pohlenz J Weiss RE
Macchia PE Pannain SLau IT Ho H et al Five new families with
resistance to thyroid hormone not caused bymutations in the thyroid hormone receptorbeta gene J Clin Endocrinol Metab1999843919ndash 28
[7] DumitrescuAM Liao XH Abdullah MS Lado-Abeal J Majed FA Moeller LC et al Muta-tions in SECISBP2 result in abnormal thyroidhormone metabolism Nat Genet2005371247ndash 52
[8] Dumitrescu AM Liao XH Best TB Brock-mann K Refetoff S A novel syndromecombining thyroid and neurological
abnormalities is associated with mutationsin a monocarboxylate transporter gene Am J Hum Genet 200474168ndash 75
[9] Friesema EC Grueters A
Biebermann HKrude H von Moers A Reeser M et alAssociation between mutations in a thyroidhormone transporter and
severe X-linked psy-chomotor retardation Lancet 20043641435ndash 7
[10] Refetoff S Bassett JH
Beck-Peccoz P Bernal JBrent G Chatterjee K et al Classificationandproposednomenclaturefor inheriteddefects ofthyroid hormone action cell transport andmetabolism Eur Thyroid J 201437ndash 9
[11] Vlaeminck-Guillem V Wemeau JL
Physiolo-gie et physiopathologie des reacutecepteurs thyr-oiumldiens lapport des modegraveles murins AnnEndocrinol (Paris) 200061440ndash 51
[12] Wikstrom L Johansson C Salto C Barlow CCampos Barros A Baas F et al Abnormalheart rate and body temperature in micelacking thyroid hormone receptor alpha 1EMBO J 199817455ndash 61
[13] Kaneshige M Suzuki H Kaneshige K Cheng J Wimbrow H Barlow C et al A targeteddominant negative mutation of the thyroidhormone alpha 1 receptor causes increasedmortality infertility and dwarfism in miceProc Natl Acad Sci U S A 20019815095ndash 100
[14] Bochukova E Schoenmakers N Agostini M
Schoenmakers E RajanayagamO Keogh JMet al A mutation in the thyroid hormonereceptor alpha gene N Engl J Med2012366243ndash 9
[15] van Mullem A van Heerebeek R Chrysis DVisser E Medici M Andrikoula M et alClinical phenotype and mutant TRalpha1 NEngl J Med 20123661451ndash 3
[16] Moran C
Schoenmakers N Agostini MSchoenmakers E Offiah A
Kydd
A et alAn adult female with resistance to thyroidhormone mediated by defective thyroid
hormone receptor alpha J Cl in EndocrinolMetab 2013984254ndash 61
[17] Moran C Agostini M Visser WE Schoen-makers E SchoenmakersN Offiah AC etalResistance to thyroid hormone caused by amutation in thyroid hormone receptor (TR)alpha1 and
TRalpha2 clinical biochemicaland genetic analyses
of three
related patientsLancet Diabet Endocrinol 20142619ndash 26
[18] van Mullem AA Chrysis D Eythimiadou AChroni E Tsatsoulis A de Rijke YB et alClinical phenotype of a new type of thyroidhormone resistance caused by a mutation ofthe TRalpha1 receptor consequences of LT4
treatment J Clin Endocrinol Metab2013983029ndash 38
[19] Yuen RK Thiruvahindrapuram B Merico DWalker S Tammimies K Hoang N et alWhole-genome sequencing of quartetfamilies with autism spectrum disorder NatMed 201521185ndash 91
[20] Tylki-Szymanska A Acuna-Hidalgo R Kra- jewska-Walasek M Lecka-Ambroziak ASteehouwer M Gi lissen C et al Thyroidhormone resistance syndrome due to muta-tions in the thyroid hormone receptor alphagene (THRA) J Med Genet 201552312ndash 6
[21] Espiard S Savagner F
Flamant F
Vlaeminck-Guillem V Guyot R Munier M
et al A novelmutation in THRA gene associated with an
atypical phenotype of resistance to thyroidhormone J Clin Endocrinol Metab 2015 jc20151120
[22] Faivre L Cormier-Daire V GenevieveD PintoG Goulet O
Munnich A
et al A novelsyndrome with dwarfism poorly muscledbuild absent clavicles humeroradial fusionslender bones oligodactyly and micro-gnathia Clin Dysmorphol 200110181ndash 4
[23] Mundlos S Cleidocranial dysplasia clinicaland molecular genetics J Med Genet199936177ndash 82
TRa receptor mutations extend the spectrum of syndromes of reduced sensitivity tothyroid hormone ENDOCRINOLOGIE
tome 44 gt n811 gt novembre2015 1 1 1 1
L i t e r a t u r e r e v i e w
7252019 Thyroid Receptors
httpslidepdfcomreaderfullthyroid-receptors 1010
[24] Mundlos S Otto F
Mundlos C Mulliken JBAylsworth AS Albright S et a l Mutat ionsinvolving the transcription factor CBFA1
causecleidocranial dysplasia Cell 199789773ndash 9
[25] Margotat A
Sarkissian G Malezet-Desmou-lins C Peyrol N Vlaeminck Guillem V
Wemeau JL
et al Ident if ication of eightnew mutations in the c-erbAB gene ofpatients with resistance to thyroid hormoneAnn Endocrinol 200162220ndash 5
[26] Adams M Matthews C Coll ingwood TNToneY
Beck-Peccoz P ChatterjeeKK Geneticanalysis of 29 kindreds with generalized andpituitary resistance to thyroid hormone Iden-tification of thirteen novel mutations in thethyroid hormone receptor beta gene J ClinInvest 199494506ndash 15
[27] Groenhout EG Dorin RI Generalized thyroidhormone resistance due to a deletion of thecarboxy terminus of the c-erbA beta receptorMol Cell Endocrinol 19949981ndash 8
[28] Wu SY CohenRN SimsekE Senses DA Yar
NE Grasberger H et al A novel thyroidhormone receptor-beta mutation that failsto bind nuclear receptor corepressor in apatient as an apparent cause of severe pre-dominantly pituitary resistance to thyroid hor-mone J Clin Endocrinol Metab 2006911887ndash 95
[29] Tinnikov A Nordstrom K Thoren P Kindblom JM Malin S Rozell B et al Retardation ofpost-natal development caused by a nega-tively acting thyroid hormone receptoralpha1 EMBO J 2002215079ndash 87
[30] Parrilla R
Mixson AJ McPherson JA
McClas-key JH Weintraub BD Characterization ofseven novel mutations of the c-erbA betagene in unrelated kindreds with generalizedthyroidhormone resistance Evidence for twohot spot regions of the l igand bindingdomain J Clin Invest 1991882123ndash 30
[31] Quignodon L VincentS Winter H Samarut JFlamant F A point mutation in the
activationfunction2 domainof thyroidhormonereceptoralpha1 expressed after CRE-mediated recom-bination partially recapitulates hypothyroid-ism Mol Endocrinol 2007212350ndash 60
[32] Liu YY
Schultz JJ
Brent GA A thyroidhormone receptor alpha gene mutation
(P398H) is associated with visceral adiposityand impaired catecholamine-stimulated lipo-lysis in mice J Biol Chem 200327838913ndash 20
[33] OShea PJ Bassett JH ChengSY Williams GRCharacterization of skeletal phenotypes ofTRalpha1 and TRbeta mutant mice implica-
tions for tissue thyroid status and T3 targetgene expression Nucl Recept Signal 20064e011
[34] OShea PJ Bassett JH Sriskantharajah S YingH Cheng SY Williams GR Contrasting ske-leta l phenotypes in mice with an identicalmutation targeted to thyroid hormone recep-tor alpha1 or beta Mol Endocrinol2005193045ndash 59
[35] Desjardin C
Charles C
Benoist-Lasselin CRiviere J Gilles M Chassande O et alChondrocytes play a major role in the stimu-lation of bone growth by thyroid hormoneEndocrinology 20141553123ndash 35
[36] Venero C Guadano-Ferraz A Herrero AINordstrom K Manzano J de Escobar GM
et al Anxiety memory impairmentand loco-motor dysfunction caused by a mutant thyr-oid hormone receptor alpha1 can beameliorated by T3 treatment Genes Dev2005192152ndash 63
[37] Pilhatsch M
Winter C
Nordstrom K Venn-strom B Bauer M
Juckel G Increaseddepressive behaviour in mice harboring themutant thyroid hormone receptor alpha 1Behav Brain Res 2010214187ndash 92
[38] Kapoor R
van Hogerlinden M
Wallis KGhosh H Nordstrom K Vennstrom Bet al Unliganded thyroid hormone receptoralpha1 impairs adult hippocampal neurogen-esis FASEB J 2010244793ndash 805
[39] Bassett JH Boyde A Zikmund T Evans HCroucher PI
Zhu X
et al
Thyroid hormonereceptor alpha mutation causes a severe
andthyroxine-resistant skeletaldysplasiain femalemice Endocrinology 20141553699ndash 712
[40] Mittag J Davis B Vujovic M Arner AVennstromB Adaptations of theautonomousnervous system controlling heart rate areimpairedby amutant thyroid hormone recep-tor-alpha1 Endocrinology 20101512388ndash 95
[41] Tavi P Sjogren M Lunde PK Zhang SJAbbate F
Vennstrom B et al Impaired
Ca2+ handling and contraction in cardiomyo-cytes from mice with a dominant negativethyroid hormone receptor alpha1 J Mol CellCardiol 200538655ndash 63
[42] Mittag J Lyons DJ Sall strom J Vujovic MDudazy-Gralla S Warner A
et al Thyroid
hormone is required for hypothalamic neu-rons regulating cardiovascular functions J ClinInvest 2013123509ndash 16
[43] Warner A RahmanA Solsjo P Gottschling KDavis B Vennstrom B et al Inappropriateheatdissipation ignitesbrown fat thermogen-esis in mice with a mutant thyroid hormonereceptor alpha1 Proc Natl Acad Sci U S A201311016241ndash 46
[44] SjogrenM AlkemadeA
MittagJ
NordstromK KatzA Rozell B etal Hypermetabolisminmice caused by the central action of an unli-ganded thyroid hormone receptor alpha1EMBO J 2007264535ndash 45
[45] Ying H Araki O Furuya F Kato Y Cheng SYImpaired adipogenesis caused by a mutated
thyroid hormone alpha1 receptor Mol CellBiol 2007272359ndash 71
[46] Araki O
Ying H Zhu XG Willingham MCChengSY Distinct dysregulationof lipid meta-bolismbyunligandedthyroid hormone recep-tor isoforms Mol Endocrinol 200923308ndash 15
[47] Liu YY
Heymann RS Moatamed F
Schultz JJSobel D Brent GA A mutant thyroid hor-mone receptor alphaantagonizesperoxisomeproliferator-activated receptor alpha signalingin vivo and impairs fatty acid oxidation Endo-crinology 20071481206ndash 17
[48] Fozzatt i L Lu C
Kim DW Cheng SY Differ-ential recruitment of nuclear coregulatorsdirects the isoform-dependent action ofmutant thyroid hormonereceptorsMol Endo-crinol 201125908
ndash 21
[49] Fozzatti
L Kim
DW
ParkJW Willingham
MCHollenberg AN Cheng SY Nuclear receptorcorepresso r (NCOR1) regulates in vivoactions ofa mutated
thyroid
hormone recep-tor alpha Proc Natl
Acad
Sci U S A20131107850ndash 5
[50] Kim DW ParkJW
Willingham MC Cheng SYA histone deacetylase inhibitor improveshypothyroidism caused by a TRalpha1mutant Hum Mol Genet 2014232651ndash 64
V Vlaeminck-Guillem S Espiard F Flamant J-LWeacutemeau
tome 44 gt n811
gt novembre 2015 1 1 1 2
L i t e r a t u r e r e v i e w
7252019 Thyroid Receptors
httpslidepdfcomreaderfullthyroid-receptors 1010
[24] Mundlos S Otto F
Mundlos C Mulliken JBAylsworth AS Albright S et a l Mutat ionsinvolving the transcription factor CBFA1
causecleidocranial dysplasia Cell 199789773ndash 9
[25] Margotat A
Sarkissian G Malezet-Desmou-lins C Peyrol N Vlaeminck Guillem V
Wemeau JL
et al Ident if ication of eightnew mutations in the c-erbAB gene ofpatients with resistance to thyroid hormoneAnn Endocrinol 200162220ndash 5
[26] Adams M Matthews C Coll ingwood TNToneY
Beck-Peccoz P ChatterjeeKK Geneticanalysis of 29 kindreds with generalized andpituitary resistance to thyroid hormone Iden-tification of thirteen novel mutations in thethyroid hormone receptor beta gene J ClinInvest 199494506ndash 15
[27] Groenhout EG Dorin RI Generalized thyroidhormone resistance due to a deletion of thecarboxy terminus of the c-erbA beta receptorMol Cell Endocrinol 19949981ndash 8
[28] Wu SY CohenRN SimsekE Senses DA Yar
NE Grasberger H et al A novel thyroidhormone receptor-beta mutation that failsto bind nuclear receptor corepressor in apatient as an apparent cause of severe pre-dominantly pituitary resistance to thyroid hor-mone J Clin Endocrinol Metab 2006911887ndash 95
[29] Tinnikov A Nordstrom K Thoren P Kindblom JM Malin S Rozell B et al Retardation ofpost-natal development caused by a nega-tively acting thyroid hormone receptoralpha1 EMBO J 2002215079ndash 87
[30] Parrilla R
Mixson AJ McPherson JA
McClas-key JH Weintraub BD Characterization ofseven novel mutations of the c-erbA betagene in unrelated kindreds with generalizedthyroidhormone resistance Evidence for twohot spot regions of the l igand bindingdomain J Clin Invest 1991882123ndash 30
[31] Quignodon L VincentS Winter H Samarut JFlamant F A point mutation in the
activationfunction2 domainof thyroidhormonereceptoralpha1 expressed after CRE-mediated recom-bination partially recapitulates hypothyroid-ism Mol Endocrinol 2007212350ndash 60
[32] Liu YY
Schultz JJ
Brent GA A thyroidhormone receptor alpha gene mutation
(P398H) is associated with visceral adiposityand impaired catecholamine-stimulated lipo-lysis in mice J Biol Chem 200327838913ndash 20
[33] OShea PJ Bassett JH ChengSY Williams GRCharacterization of skeletal phenotypes ofTRalpha1 and TRbeta mutant mice implica-
tions for tissue thyroid status and T3 targetgene expression Nucl Recept Signal 20064e011
[34] OShea PJ Bassett JH Sriskantharajah S YingH Cheng SY Williams GR Contrasting ske-leta l phenotypes in mice with an identicalmutation targeted to thyroid hormone recep-tor alpha1 or beta Mol Endocrinol2005193045ndash 59
[35] Desjardin C
Charles C
Benoist-Lasselin CRiviere J Gilles M Chassande O et alChondrocytes play a major role in the stimu-lation of bone growth by thyroid hormoneEndocrinology 20141553123ndash 35
[36] Venero C Guadano-Ferraz A Herrero AINordstrom K Manzano J de Escobar GM
et al Anxiety memory impairmentand loco-motor dysfunction caused by a mutant thyr-oid hormone receptor alpha1 can beameliorated by T3 treatment Genes Dev2005192152ndash 63
[37] Pilhatsch M
Winter C
Nordstrom K Venn-strom B Bauer M
Juckel G Increaseddepressive behaviour in mice harboring themutant thyroid hormone receptor alpha 1Behav Brain Res 2010214187ndash 92
[38] Kapoor R
van Hogerlinden M
Wallis KGhosh H Nordstrom K Vennstrom Bet al Unliganded thyroid hormone receptoralpha1 impairs adult hippocampal neurogen-esis FASEB J 2010244793ndash 805
[39] Bassett JH Boyde A Zikmund T Evans HCroucher PI
Zhu X
et al
Thyroid hormonereceptor alpha mutation causes a severe
andthyroxine-resistant skeletaldysplasiain femalemice Endocrinology 20141553699ndash 712
[40] Mittag J Davis B Vujovic M Arner AVennstromB Adaptations of theautonomousnervous system controlling heart rate areimpairedby amutant thyroid hormone recep-tor-alpha1 Endocrinology 20101512388ndash 95
[41] Tavi P Sjogren M Lunde PK Zhang SJAbbate F
Vennstrom B et al Impaired
Ca2+ handling and contraction in cardiomyo-cytes from mice with a dominant negativethyroid hormone receptor alpha1 J Mol CellCardiol 200538655ndash 63
[42] Mittag J Lyons DJ Sall strom J Vujovic MDudazy-Gralla S Warner A
et al Thyroid
hormone is required for hypothalamic neu-rons regulating cardiovascular functions J ClinInvest 2013123509ndash 16
[43] Warner A RahmanA Solsjo P Gottschling KDavis B Vennstrom B et al Inappropriateheatdissipation ignitesbrown fat thermogen-esis in mice with a mutant thyroid hormonereceptor alpha1 Proc Natl Acad Sci U S A201311016241ndash 46
[44] SjogrenM AlkemadeA
MittagJ
NordstromK KatzA Rozell B etal Hypermetabolisminmice caused by the central action of an unli-ganded thyroid hormone receptor alpha1EMBO J 2007264535ndash 45
[45] Ying H Araki O Furuya F Kato Y Cheng SYImpaired adipogenesis caused by a mutated
thyroid hormone alpha1 receptor Mol CellBiol 2007272359ndash 71
[46] Araki O
Ying H Zhu XG Willingham MCChengSY Distinct dysregulationof lipid meta-bolismbyunligandedthyroid hormone recep-tor isoforms Mol Endocrinol 200923308ndash 15
[47] Liu YY
Heymann RS Moatamed F
Schultz JJSobel D Brent GA A mutant thyroid hor-mone receptor alphaantagonizesperoxisomeproliferator-activated receptor alpha signalingin vivo and impairs fatty acid oxidation Endo-crinology 20071481206ndash 17
[48] Fozzatt i L Lu C
Kim DW Cheng SY Differ-ential recruitment of nuclear coregulatorsdirects the isoform-dependent action ofmutant thyroid hormonereceptorsMol Endo-crinol 201125908
ndash 21
[49] Fozzatti
L Kim
DW
ParkJW Willingham
MCHollenberg AN Cheng SY Nuclear receptorcorepresso r (NCOR1) regulates in vivoactions ofa mutated
thyroid
hormone recep-tor alpha Proc Natl
Acad
Sci U S A20131107850ndash 5
[50] Kim DW ParkJW
Willingham MC Cheng SYA histone deacetylase inhibitor improveshypothyroidism caused by a TRalpha1mutant Hum Mol Genet 2014232651ndash 64
V Vlaeminck-Guillem S Espiard F Flamant J-LWeacutemeau
tome 44 gt n811
gt novembre 2015 1 1 1 2
L i t e r a t u r e r e v i e w