Glycosylation disorders – April 14 2009 › ~glycobiology › CCRC course (Hennet).pdf ·...

CCRC Course on Glycobiology

Glycosylation disorders – April 14 2009

Presentation ................................................................................... page 2

Summary table ............................................................................... page 46

Proposal for new nomenclature ..................................................... page 49

Mutations in lipid-linked oligosaccharide biosynthesis ................... page 51

Thierry Hennet, PhD University of Zürich Institute of Physiology Winterthurerstrasse 190 CH-8057 Zürich [email protected]

mailto:[email protected]�

CCRC course on Glycobiology

Glycosylation disorders

Thierry Hennet, University of Zürich

Glycosylation disorders

Primary glycosylation disorders

Mutations in glycosylation genes

Secondary glycosylation disorders

Galactosemia

Fructosemia

Alcool abuse

Intoxication

Astragalus lentiginosus

Defects in specific glycosylation classesCongenital muscular dystrophiesEhlers-Danlos (progeroid form)Multiple hereditary exostosesFamilial tumoral calcinosisSpondylocostal dysostosisInfantile-onset symptomatic epilepsy syndromePeters Plus SyndromeAutosomal dominant polycystic liver diseaseParoxysmal nocturnal hemoglobinuriaCongenital disorders of glycosylation-I

Defects across glycosylation classesHereditary inclusion body myopathyCOG deficiencyCongenital disorders of glycosylation-IIc and -IId

Golgi stack

Glycosyltransferase reaction

NDP-sugar + Acceptor NDP + Acceptor-sugar

NDP-sugar

NDP-sugar

AcceptorNDP

Acceptor-sugar

NMP

NMP

Pi

H+

Mn2+Nature Genetics 40, 32 - 34 (2008)

Biosynthesis of nucleotide-sugars

Gal-1-P

UDP-Gal

Glc-1-P

Glc-6-P

DolP-Glc

UDP-Glc

Fru-6-P GlcNAc-6-P

GlcNAc-1-P

UDP-GlcNAc

ManNAc

ManNAc-6-P

Sia-9-P

Sia

CMP-Sia

Man-6-P

Man-1-P

GDP-Man

DolP-Man

Fuc-1-P

GDP-Fuc

Gal Fru GlcNAc Man FucGlc

UDP-GlcA

UDP-Xyl

UGD

GMDS

GFAT

GNE

Hereditary inclusion body myopathy andsialuria

N CUDP-GlcNAc 2-epimerase domain

ManNAc kinase domain

GNE:

adult-onset muscular weaknessaffects mainly leg muscles (without quadriceps)origin and constitution of vacuoles unknown

Hereditary inclusion body myopathy

accumulation and excretion of free sialic acidhepatosplenomegalyfrequent upper respiratory infections in infancy

Sialuria

N-glycans O-glycans C-glycans

GAG GPIanchor

Glycolipids Cytoplasmic/nuclearglycans

N S/T S/T S/T W

Cer CerPI S/TS

S/T Hyl

Glycoconjugate classes in vertebrates

αβ

β

α β α β α

ββ βα

α

α

α

ββ

β

β

β

β

α α

O-GalNAc and mucins

Dense "sugar coating“ considerable water-holding capacity resistant to proteolysis (important in maintaining mucosal barriers).

Mucins are secreted as massive aggregates with MW of roughly 1 to 10 mio Da.

S/T S/T S/T

ppGalNAcT defect

S/TppGalNAcT3

Mutations in ppGalNAcT3 cause familial tumoral calcinosisTopaz et al. (2004) Nat. Genet. 36, 579 – 581

FGF23 glycosylation

FGF23

FGF-Receptor 1c

subtilisin-like proproteinconvertase (SPC)

ppGalNAcT3

RHTR

Vitamin D

7-Dehydroxycholesterol Previtamin D3

Vitamin D3Skin

25(OH)D3

Vitamin D

1,25(OH)2D3

Vitamin D-25-hydroxylase

HO

1α-hydroxylase

UV light(290-315 nm)

heat

diet

PlacentaKeratinocytesMacrophages

low Ca2+

low PO43+

PTHProlactinGrowth hormoneCalcitoninhCSHigh Ca2+,

high PO43+

FGF23T3, T4

Stimulates intestinal Ca2+ absorptionInhibits PTH secretionStimulates RANK-L formation in osteoblastsActivates macrophagesDecreases renin secretionIncreases insulin secretion


GAG GPIanchor


N S/T S/T S/T W

Cer CerPI S/TS

S/T Hyl


αβ

β

α β α β α

ββ βα

α

α

α

ββ

β

β

β

β

α α

Diseases of O-mannosylation

• Walker-Warburg syndrome • “Muscle-Eye-Brain” disease• Fukuyama muscular dystrophy

Congenital Muscular Dystrophies (CMD)„Cobblestone“ Lissencephalies

α

γ δ εα ββ

Laminin 2

Sarcoglycan

F-Actin

Synthrophins

Dystrobrevin

Muskelmembran

Extrazelluläre Matrix

α

γ δ εα ββ

Laminin 2Dystroglycan

Dystrophin

Muscle membrane

Extracellular Matrix

O-GalNAc chains

O-Man chains

Dystroglycan defects

• Walker-Warburg syndrome • “Muscle-Eye-Brain” disease• Fukuyama muscular dystrophy

POMT1POMGnT1FukutinFukutin-related protein (FRP)Large

POMT1/POMT2

POMGnT1

Fukutin

LARGE

FKRP

Walker Warburg

Muscle eye brain

FCMD

MDC1D

MDC1C

Limb girdle MD

CMD +MR

Extent of residual α-DG glycosylation likely to be important

Severity

For recent genotype/phenotype correlation studySee Godfrey et al. Brain 130:2725-2735 (2007)

Gene/phenotype relationships


GAG GPIanchor


N S/T S/T S/T W

Cer CerPI S/TS

S/T Hyl


αβ

β

α β α β α

ββ βα

α

α

α

ββ

β

β

β

β

α α

P P

FGF2 FGF2

FGF2

HGF

ProteoglycanFGF2-Receptor

Diseases of glycosylation: exostoses

EXT1 (chr 8q24)EXT2 (chr 11p12)EXT3 (chr 19p)

B4GALT7 (chr 5q32)

00FGF18

FGF2

BMPs

Normal Exostoses

Endochondral ossification


GAG GPIanchor


N S/T S/T S/T W

Cer CerPI S/TS

S/T Hyl


αβ

β

α β α β α

ββ βα

α

α

α

ββ

β

β

β

β

α α

Enzymes of O-fucosylation/glucosylation

S/T

6 β4GalT

3 β3GlcNAcT

3 ST3GalT

1 β3GlcT 2 OFUT

lunatic fringeradical fringemanic fringe

S/T

XylT genes notcloned yet

1 OGLCT

Peters Plus syndrome

Figure 2 from Oberstein et al.

Peters Plus syndrome is caused by mutations in B3GALTL, a putative glycosyltransferase.Oberstein et al. (2006) Am J Hum Genet, 79:562-566

Birth weight below 3rd percentile, psychomotor retardation, hypertelorism, short limbs, short hands, eye anterior chamber defect

Diseases of O-fucosylation

Mutations in DLL3 (ligand of Notch) also causes spondylocostal dysostosis in humans (OMIM 602768)

Hes7

Lunatic fringe disruption causes spondylocostal dysostosis in the mouse and in humans (OMIM 609813).See: Evrard Y.A. et al. (1998) Nature 394, 377 – 381


GAG GPIanchor


N S/T S/T S/T W

Cer CerPI S/TS

S/T Hyl


αβ

β

α β α β α

ββ βα

α

α

α

ββ

β

β

β

β

α α

failure to thrivepsychomotor retardationhypotoniacerebellum hypoplasiaataxiahormonal disordersepilepsystrabismuscoagulation disorderstissue fibrosis

CDG

Congenital disorders of glycosylation

Serum transferrin isoelectric focusing (IEF)

AsnAsn

MM M

GG

G G GGG

S SGS

MM M

GG

G G GGG

S SGS

CDG-IICDG-I

N

N N N

N

ER

Golgi

N-Glycosylation

=G

== M =dolichol

glucosemannoseGlcNAc

Lumen

PG

Cytoplasm UDP-

N-linked glycosylation: the ER pathway

GP P

G UDP

M

M

P

PM

GDP- GDPM

PP

GDP

CTP CDPUMPUDP

UDP

UDP

MM

MM

M

MM

M

M

GDP

M

MMM

M

GDP-M

MMM

MM

M

MMM

MM

M

MMM

MMM

M

MMM

MMM

M M

MMM

MMM

MM

M

MMM

MMM

MM

GG

M

MMM

MMM

MM

G

GG

M

MMM

MMM

MM

G

SEC59 DPM1 ALG5ALG7

ALG1

OST

ALG2

ALG11

ALG11 RFT1ALG3

ALG9ALG12

ALG9ALG6

ALG8ALG10

G

M

MMM

MMM

MM

G

G

ALG13ALG14

0 15 30 45 60 75 (min)

3252

2439

1626

813

0

0 15 30 45 60 75 (min)

1200

900

600

300

0

0 15 30 45 60 75 (min)

366

275

184

93

0

(dpm)

(dpm)

(dpm)

Marker

CDG-Ic Patient

Control cells

M5M8

G3M9

G3M9

M9

G

M

MMM

MM M

MM

G

G

M

MMM

MM M

MM

Lipid-linked oligosaccharides (LLO)

=G

== M =dolichol

glucosemannoseGlcNAc

SEC59

Lumen

DPM1 ALG5

PG

Cytoplasm

ALG7

ALG1

UDP-

OST

GP P

G UDP

M

M

P

PM

GDP- GDPM

PP

GDP

CTP CDPUMPUDP

UDP

UDP

ALG2

MM

MM

M

ALG11

MM

M

M

GDP

M

MMM

M

GDP-M

ALG11

MMM

MM

M

MMM

MM

RFT1ALG3

M

MMM

MMM

ALG9

M

MMM

MMM

M M

MMM

MMM

MM

ALG12ALG9

M

MMM

MMM

MM

ALG6

GG

M

MMM

MMM

MM

G

GG

M

MMM

MMM

MM

G

ALG8ALG10

G

M

MMM

MMM

MM

G

G

Glycosylation defect in CDG-Ic

ALG13ALG14

ScAlg6: MAIGKRLLVNKPAEESFYASPMYDFLYPFRPVGNQWLPEYIIFVCAVILRCTIGLGPYSG HsAlg6: --------------------------------MEKWYLMTVVVLIGLTVRWTVSLNSYSG

ScAlg6: KGSPPLYGDFEAQRHWMEITQHLPLSKWYWY----DLQYWGLDYPPLTAFHSYLLGLIGS HsAlg6: AGKPPMFGDYEAQRHWQEITFNLPVKQWYFNSSDNNLQYWGLDYPPLTAYHSLLCAYVAK

ScAlg6: FFNPSWFALEKSRGFESPDNGLKTYMRSTVIISDILFYFPAVIYFTKWLGRYRNQSPIGQ HsAlg6: FINPDWIALHTSRGYES--QAHKLFMRTTVLIADLLIYIPAVVLYCCCLKEISTKKKIAN H ScAlg6: SIAASAILFQPSLMLIDHGHFQYNSVMLGLTAYAINNLLDEYYAMAAVCFVLSICFKQMA HsAlg6: ---ALCILLYPGLILIDYGHFQYNSVSLGFALWGVLGISCDCDLLGSLAFCLAINYKQME I ScAlg6: LYYAPIFFAYLLSRSLLFPKFNIARLTVIAFATLATFAIIFAPLYFLGGGLKNIHQCIHR HsAlg6: LYHALPFFCFLLGKCFKKGLKGKGFVLLVKLACIVVASFVLCWLPFFTE-REQTLQVLRR E ScAlg6: IFPFARGIFEDKVANFWCVTNVFVKYKERFTIQQLQLYSLIATVIGFLPAMIMTLLHPKK HsAlg6: LFPVDRGLFEDKVANIWCSFNVFLKIKDILPRHIQLIMSFCFTFLSLLPACIKLILQPSS ∆ S R ScAlg6: HLLPYVLIACSMSFFLFSFQVHEKTILIPLLPITLLYSSTDWNVLSLVSWINNVALFTLW HsAlg6: KGFKFTLVSCALSFFLFSFQVHEKSILLVSLPVCLVLS----EIPFMSTWFLLVSTFSML V ScAlg6: PLLKKDGLHLQYAVSFLLSNWLIGNFSFITPRFLPKSLTPGPSISSINSDYRRRSLLPYN HsAlg6: PLLLKDELLMPSVVTTMAFFIACVTSFSIFEKTSEEELQLKSFSISVRKYLPCFTFLSRI

ScAlg6: VVWKSFIIGTYIAMGFYHFLDQFVAPPSKYPDLWVLLNCAVGFICFSIFWLWSYYKIFTS HsAlg6: IQYLFLIS--VITMVLLTLMTVTLDPPQKLPDLFSVLVCFVSCLNFLFFLVYFNIIIMWD ∆ P ScAlg6: GS--KSMKDL- HsAlg6: SKSGRNQKKIS

ALG6 protein alignment

wildtype Hefe

YEp352

ScALG6

HsALG6

HsALG6[A333V]

HsALG6[F304S]

HsALG6[S478P]

HsALG6[F304S][S478P]

alg6wbp1-2 +

ALG6 complementation: growth phenotype

YeastHumans

PPCDG-Ic patient alg6 Strain

Identification of mutationsin ALG6 gene of CDG Patients

human ALG6 gene

functional analysis of mutationsin yeasts

ALG6 glucosyltransferasedeficiency

normal yeasts

alg6 yeasts

alg6 yeasts + human ALG6 gene

alg6 yeasts + ALG6 gene from CDG patients

N

OST

OST defect in non-syndromic mental retardation

G

M

MMM

MMM

MM

G

G

G

M

MMM

MMM

MM

G

G

endoplasmicreticulum

OST3/6

“Diseases” of Golgi N-glycosylation

N

CDG-IIa (GnT2)

CDG-IId (B4GALT1)

CDG-IIc (FUCT1)

FUT3/6 deficiency

GnT2 defect in CDG-IIa

GDG-IIa patients Mgat2-null mice

Failure to thrive Runted, low postnatal survival

Facial dysmorphy Facial dysmorphy

Osteopenia Osteopenia

psychomotor retardation Defective locomotor activity

Epilepsy Tremors and seizures

Blood coagulaopathy Blood coagulopathy

Testicular atrophy Testicular atrophy

Splenomegaly Splenomegaly

Susceptibility to infections glomerulonephritis

Branching defects

N

∆GnT1: embryonic lethality

∆GnT2: peri-natal lethality (CDG-IIa)

∆GnT3: no phenotype found so far

∆GnT4: type 2 diabetes

∆GnT5: T-cell hyperreactivity,endocytosis of membranereceptors

M1V

N

C

frameshift(stop AA34)

C9YF11C

G15R, G15EG15A

T18S

P20S

Ex skip

L32R

L35X

Q37H

V44AV44F

K51R


Ex skip

Y64CD65Y

V67MV67G

P69S

Y76CEx skip

E93A

N101K

C103FL104V

Y106C

A108Vframeshift(stop AA126)

P113L

G117R

F119LI120T

R123XR123Q

V129M


P131A

I132TI132NI132F


E139K

R141H / R141C

F144L D148N


I153T

E151G F157S

R162W

F172VG176V

G175RQ177H

F183SD185G D188G

frameshift (stop AA199)

C192G

R194XH195R

E197A

F206T, F206LF207SG208A

G214SEx skip

del ex8ins 41AA

N216I / N216SD217E

H218L

D223ED223N

T226S

G228 CG228R

Y229S

V231M A233T

R238G / R238P

T237RT237M

R239WC241S

L243P

R21GQ22X

G42R

G57R

PMM2

A selection pressure for glycosylation defects?

Carrier frequency of 1 in 70!

Diagnose

A

B

AB

O

Anti-BSerum

Anti-ASerum

Anti-AAnti-BSerum

GalFuc

GlcNAc

Gal

GalFuc

GlcNAc

GalFuc

GlcNAc

GalNAc

O A B

The ABO-System:

Glycan polymorphisms: ABO blood groups

Loss of α1-3 GalT in Old-World primates

GlcNAc

Gal

R

GlcNAc

Gal

R

Gal

α1-3 GalT

Loss of CMP-Neu5Ac hydroxylase in humans

Norovirus

CBC News – Canada Friday, January 19, 2007

Saskatoon's Royal University Hospital, the city's biggest, was closed to visitors Friday after an outbreak of Norwalk virus. More than 40 patients and staff have fallen ill with the norovirus infection. Managers are trying to contain the outbreak.The virus is easily spread on surfaces and through the air. Symptoms include severe stomach cramps, vomiting and diarrhea. The illness is rarely fatal, but it can be a serious health concern for seniors and babies.

Caliciviridae family38 nm diameterSimple structure (single capsid protein, non-enveloped)7.5 kb genome (single stranded, positive sensed RNA)

B enzymeA enzyme

FUT3

FUT2FUT3

Norovirus binding specificity

Gal

GlcNAc

β

Fuc

Gal

GlcNAc

β

α Gal

GlcNAc

β

Fuc

α

Lea H

Gal

GlcNAc

β

Fuc

α

Fuc

α

Leb

GalNAc

Gal

GlcNAc

β

Fuc

α

α

Gal

GlcNAc

β

Fuc

α

α

Gal

Fuc

α

GalNAc

Gal

GlcNAc

β

Fuc

α

α

Gal

GlcNAc

β

Fuc

α

α

Gal

Fuc

α

FUT3

A B

A Leb B Leb

FUT3

BoxerVA207OIF

VA387 PiVGrV MxVNorwalk HawaiC59 MOHBUDS SMV

Lewis binding group

A/B binding group

Blood group binding pattern

Huang, P.W. et al. (2005) J. Virol. 79:6714-22

The Red Queen effect

"Well, in our country," said Alice, still panting a little, "you'd generally get to somewhere else — if you run very fast for a long time, as we've been doing.„

"A slow sort of country!" said the Queen. "Now, here, you see, it takes all the running you can do, to keep in the same place. If you want to get somewhere else, you must run at least twice as fast as that!"

Lewis Carroll, Through the Looking-Glass

Table I. Diseases of glycosylation

Name Gene defect Activity OMIM

N-glycosylation

CDG-Ia PMM2 phosphomannomutase (Man-6-P Man-1-P) 212065

CDG-Ib PMI phosphomannose isomerase

(Fru-6-P Man-6-P)

602579

CDG-Ic ALG6 α1-3 glucosyltransferase 603147

CDG-Id ALG3 α1-3 mannosyltransferase 601110

CDG-If MPDU1 unknown 609180

CDG-Ig ALG12 α1-6 mannosyltransferase 607143

CDG-Ih ALG8 α1-3 glucosyltransferase 608104

CDG-Ii ALG2 α1-3 mannosyltransferase 607905

CDG-Ij DPAGT1 N-acetylglucosamine-1-phosphate transferase 608093

CDG-Ik ALG1 β1-4 mannosyltransferase 608540

CDG-IL ALG9 α1-2 mannosyltransferase 608776

CDG-In RFT1 lipid-linked oligosaccharide flipping 612015

“CDG-Io” TUSC3/OST3 oligosaccharyltransferase 601385

“CDG-Ip” IAP/OST6 oligosaccharyltransferase -

CDG-IIa MGAT2 β1-2 N-acetylglucosaminyltransferase 212066

CDG-IIb GLS1 α1-2 glucosidase 606056

O-GalNAc glycosylation

Familial tumoral

calcinosis

GALNT3 polypeptide N-acetylgalactosaminyl-

transferase

211900

Tn syndrome COSMC β1-3 galactosyltransferase chaperone 300622

O-Man glycosylation

Walker-Warburg

syndrome

POMT1 and

POMT2

protein O-mannosyltransferase 236670

Muscle-Eye-Brain

disease

POMGNT1 β1-2 N-acetylglucosaminyltransferase 253280

Fukuyama congenital

muscular dystrophy

FKTN unknown 253800

MDC1C FKRP unknown 606612

limb-girdle muscular

dystrophy

FKRP unknown 607155

MDC1D LARGE unknown 608840

O-Fuc glycosylation

Spondylocostal

dysostosis

LFNG β1-3 N-acetylglucosaminyltransferase 277300

Peters-Plus syndrome B3GALTL β1-3 glucosyltransferase 261540

GAG chains

Ehlers-Danlos syndrome

(progeroid form)

XGPT1 xylose β1-4 galactosyltransferase 130070

hereditary Multiple

exostoses-I

EXT1 proteoglycan β1-4 glucuronyl/α1-4 N-

acetylglucosaminyl-transferase

133700

hereditary Multiple

exostoses-II

EXT2 proteoglycan β1-4 glucuronyl/α1-4 N-

acetylglucosaminyl-transferase

133701

Schneckenbecken

dysplasia

SLC35D1 solute carrier family 35 (UDP-glucuronic

acid/UDP-N-acetylgalactosamine dual

transporter), member D1

610804

Glycosphinglolipids and GPI anchor

Amish infantile epilepsy

syndrome

ST3GAL5 α2-3 sialyltransferase (GM3 synthase) 609056

Paroxysmal nocturnal

hemoglobinuria

PIGA glycosylphosphatidylinositol (GPI)

N-acetylglucosaminyltransferase

311770

Multiple classes of glycosylation

CDG-Ie DPM1 dolichol-phosphate-mannose synthase

(GDP-Man Dol-P-Man)

608799

“CDG-Iq” DPM2 dolichol-phosphate-mannose synthase

(GDP-Man Dol-P-Man)

603564

“CDG-Ir” DPM3 dolichol-phosphate-mannose synthase

(GDP-Man Dol-P-Man)

605951

CDG-IIc SLC35C1 import of GDP-Fuc into Golgi and export of

GMP

266265

CDG-IId B4GALT1 β1-4 galactosyltransferase 607091

CDG-IIf SLC35A1 import of CMP-Sia into Golgi 603585

Hereditary inclusion

body myopathy

GNE UDP-N-acetylglucosamine 2-epimerase 600737

CDG-Im DK1 dolichol kinase 610768

“CDG-Is” pending dolichol reductrase unpublished

Trafficking disorders

CDG-IIe COG7 vesicular trafficking 608779

CDG-IIg COG1 vesicular trafficking 611209

CDG-IIh COG8 vesicular trafficking 611182

CDG-IIi COG4 vesicular trafficking unpublished

CDG-IIj COG5 vesicular trafficking unpublished

Autosomal recessive

cutis laxa

ATPV0A2 H+/ATPase, pH regulation in Golgi 219200

CDG nomenclature: time for a change! Jaak Jaeken1,2, Thierry Hennet3 , Gert Matthijs4, Hudson Freeze5

2Center for Metabolic Disease, Katholieke Universiteit Leuven, BE-3000 Leuven, Belgium 3Institute of Physiology, University of Zürich, CH-8057 Zürich, Switzerland 4Center for Human Genetics, Katholieke Universiteit Leuven, BE-3000 Leuven, Belgium 5Sanford Children’s Health Research Center, Burnham Institute of Research, La Jolla, CA 92037, USA 1To whom correspondence should be addressed: Tel: +32 16 343820; Fax: +32 16 343842; e-mail: jaak [email protected] Congenital disorders of glycosylation (CDG) are a rapidly growing disease family with nearly 40 diseases reported since its first clinical description in 1980 (1). The large majority of these are diseases of protein hypoglycosylation, but in recent years several defects in lipid glycosylation have also been identified (2,3). Most protein glycosylation disorders are due to defects in the N-glycosylation pathway, the remaining ones affecting the O-glycosylation disorders or combined N- and O-glycosylation pathways. No defects in C-glycosylation have been detected yet. The first described CDG patients were shown to have an abnormal serum transferrin (Tf) isoelectrofocusing (IEF) pattern with increases in the di- and asialotransferrin fractions (4 ). They were found to have deficient phosphomannomutase (PMM) activity (5) and mutations in the PMM2 gene (6). PMM deficient patients were designated as CDG-Ia. Subsequently, a patient was discovered with a serum Tf IEF pattern characterized by increases not only of the even (2 and 0) but also of the uneven (3 and 1) sialoTf bands (7). Since these patterns were qualitatively different, we called the latter a type 2 pattern as opposed to the type 1 pattern seen in PMM deficiency. In the patient with the type 2 pattern, a deficiency was demonstrated to be in a Golgi glycosyltransferase, namely N-acetylglucosaminyltransferase II (8). This disease was labelled CDG-IIa. New patients were classified as CDG-I or CDG-II according to the Tf IEF pattern, and each new defect took the next letter of the alphabet.

We presently count 14 CDG-I diseases (CDG-Ia up to CDG-In), and 8 CDG-II diseases (CDG-IIa up to CDG-IIh). Since this nomenclature is based on the Tf IEF pattern, it relates only to N-glycosylation diseases associated with deficient sialylation. Gradually it became clear that CDG-I defects were limited to defects in pre-ER or ER proteins whereas CDG-II defects were caused by defects in Golgi or Golgi-associated proteins. However, some of these disorders also show abnormal O-glycosylation such as the COG defects (review in 9) and the V-ATPase defect in cutis laxa type II (10). Also, it appeared that a patient with an alpha-glucosidase-II deficiency in the ER had a normal Tf IEF pattern (11). Still this patient was labeled as CDG-IIb, which is an inconsistency of this classification. For this reason and for a number of other reasons explained elsewhere (12 ), we strongly suggest that this

nomenclature should be discontinued in favour of a transparent designation of glycosylation disorders and that it be applied to new and established types of CDG. We propose using only the official gene name, with the option of adding CDG in parentheses after the gene name (list of approved gene names at http://www.genenames.org). A classification of the known types of CDG, along with the traditional and new nomenclature, is shown in the Table (12).

References

1. Jaeken J, Vanderschueren-Lodeweyckx M, Casaer P, et al. Familial psychomotor retardation with markedly fluctuating serum prolactin, FSH and GH levels, partial TBG deficiency, increased serum arylsulfatase A and increased CSF protein: a new syndrome? Pediatr Res 1980; 14: 179

2. Freeze HH. Genetic defects in the human glycome. Nat Rev Genet 2006; 7: 537-551 3. Jaeken J, Matthijs G. Congenital disorders of glycosylation: a rapidly expanding

disease family. Annu Rev Genomics Hum Genet 2007; 8: 261-278 4. Jaeken J, van Eijk HG, van der Heul C, Corbeel L, Eeckels R, Eggermont E. Sialic

acid-deficient serum and cerebrospinal fluid transferrin in a newly recognized genetic syndrome. Clin Chim Acta 1984; 144: 245-247

5. Van Schaftingen E, Jaeken J. Phosphomannomutase deficiency is a cause of carbohydrate-deficient glycoprotein syndrome type I. FEBS Lett 1995; 377: 318-320

6. Matthijs G, Schollen E, Pardon E, et al. Mutations in PMM2, a phosphomannomutase gene on chromosome 16p13, in carbohydrate-deficient glycoprotein type I syndrome (Jaeken syndrome). Nat Genet 1997; 16: 88-92. Erratum in Nat Genet 1997; 16: 316

7. Ramaekers VT, Stibler H, Kint J, Jaeken J. A new variant of the carbohydrate deficiënt glycoproteins syndrome. J Inherit Metab Dis 1991; 14: 385-388

8. Jaeken J, Schachter H, Carchon H, De Cock P, Coddeville B, Spik G. Carbohydrate deficiënt glycoprotein syndrome type II: a deficiency in Golgi localised N-acetylglucosaminyltransferase II. Arch Dis Child 1994; 71: 123-127

9. Zeevaert R, Foulquier F, Jaeken J, Matthijs G. Deficiencies in subunits of the Conserved Oligomeric Golgi complex define a novel group of Congenital Disorders of Glycosylation. Mol Genet Metab 2008; 93: 15-21

10. Kornak U, Reynders E, Dimopoulou A, et al. Impaired glycosylation and cutis laxa caused by mutations in the vesicular H+-ATPase subunit ATP6V0A2. Nat Genet 2008; 40: 32-34

11. De Praeter CM, Gerwig GJ, Bause E, et al. A novel disorder caused by defective biosynthesis of N-linked oligosaccharides due to glucosidase I deficiency. Am J Hum Genet 2000; 66: 1744-1756

12. Jaeken J, Hennet T, Freeze H, Matthijs G. About nomenclature of Congenital Disorders of Glycosylation (CDG). J Inherit Metab Dis 2008 Oct 24 (Epub ahead of print)

M1V

N

C


C9YF11C

G15R, G15EG15A

T18S

P20S

Ex skip

L32R

L35X

Q37H

V44AV44F

K51R


Ex skip

Y64CD65Y

V67MV67G

P69S

Y76CEx skip

E93A

N101K

C103FL104V

Y106C

A108Vframeshift(stop AA126)

P113L

G117R

F119LI120T

R123XR123Q

V129M


P131A

I132TI132NI132F


E139K

R141H / R141C

F144L D148N


I153T

E151G F157S

R162W

F172VG176V

G175RQ177H

F183SD185G D188G

frameshift (stop AA199)

C192G

R194XH195R

E197A

F206T, F206LF207SG208A

G214SEx skip

del ex8ins 41AA

N216I / N216SD217E

H218L

D223ED223N

T226S

G228 CG228R

Y229S

V231M A233T

R238G / R238P

T237RT237M

R239WC241S

L243P

R21GQ22X

G42R

G57R

PMM2 (phosphomannomutase)

cytosol

N

M51T



S102L

Y129C

D131N I140T

M138T

R152Q

E156K

R219Q

G250S

Y255C

R295H

I398T

C

R418HR418C

splicing

PMI (phosphomannose isomerase)

cytosol

N

C

C99S

Y441S

DOLK (Dol kinase)

cytosol

ER lumen

N C

Splicing(c.162-8 G>A)

Y170C

I297F

ALG7 (GlcNAc-1-phosphate transferase)

cytosol

ER lumen

ALG1 (β1-4 mannosyltransferase)

N

C

S258L

Ex skip

Q342P

G145D

S150R

D249E

R438W

M377V

L396X

cytosol

ER lumen

N

CK131N


ALG2 (α1-3 mannosyltransferase)

cytosol

ER lumen

C

N

R67C

K152E

E298K

I296K, I296R

RFT1 (Dol-PP-GlcNAc2Man5 flipping)

cytosol

ER lumen

DPM1

NC

DPM2 DPM3

NC

N

C

R92G


splicing

N169S


S248P

DPM (Dol-P-Man synthase)

cytosol

ER lumen

N C

G73E

M1T

L74S

L119P


MPDU1 (unknown function)

cytosol

ER lumen

N

C

P39L

Splicing

W71R

Y88H

G118D

M157K

R171Q

R266C

R266C


cytosol

ER lumen

N

C

Y287C

E530K


cytosol

ER lumen

N

C

T67M


A81T

G101R

F142V

R146Q

L158P

Y230D

S275N

R311C

Y414X


cytosol

ER lumen

N

C

R113H

Y57X

S170I

G227E

∆I299

S308R

A333V∆L444

S478P

splicing

R18Q

splicing

splicing ∆C303

ALG6 (α1-3 glucosyltransferase)

cytosol

ER lumen

N

C

T47P


splicing P69L


N222S

splicing

splicing

G275D

R364X

ALG8 (α1-3 glucosyltransferase)

cytosol

ER lumen

Glycosylation disorders – April 14 2009 › ~glycobiology › CCRC course (Hennet).pdf ·...

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