Genetische heterogeniteit bij Osteogenesis Imperfecta Een ...
Osteogenesis Imperfecta COL1A1
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Transcript of Osteogenesis Imperfecta COL1A1
OSTEOGENESIS IMPERFECTA
COL1A1
Katelynn Weber
OSTEOGENESIS IMPERFECTA Characteristics 6/100,000
worldwide
DIAGNOSIS Child Abuse? Clinical symptom
evaluation, DNA and protein testing to confirm
Family history Ultrasound and
amniocentesis performed in utero
90% of mutations in collagen 1
Types II, III, IV often born with broken bones
COL1A1 17q21.33 Osteogenesis
imperfecta types I-IV Ehlers-Danlos Osteoporosis
COL1A1 Collagen, type 1, alpha 1 Type 1 collagen is the most abundant in the
human body Provides strength and support for cartilage,
bone, tendon, skin, and sclera COL1A1 codes for pro-α1(I) component of
collagen
COLLAGEN
MUTATION OI is most common result of COL1A1
mutations Mildest for of OI results from reduced
production of pro-α1(I) chains More severe types (II, III, IV):
Deleted segments of DNA within COL1A1 Altered aa sequence—replacement of glycine AA substitutions alter C-terminus of protein
Abnormal collagen incorporated into bones causing severe forms of OI
TESTING To detect mutations that alter mRNA stability Genomic DNA sequence analysis
Nonsense, missense, splice-site Type IV (70-80%)
Complementary DNA sequence analysis RNA derived from dermal fibroblasts; sometimes
leukocytes Missense, small insertions/deletions, exon-
skipping Types I (100%), II(98%), III (60-70%)
Mutations in most families are unique; only few recurrent mutations seen in more than one family
INHERITANCE Autosomal Dominant
Types I-V Autosomal Recessive
Type VII, sometimes III* *Often indicates mutations in other genes (CRTAP
or LEPRE1) No history
Type II and III often present with no family history Sporadic mutations in COL1A1 and COL1A2
Children of proband have 50% chance of inheriting OI
OVERVIEW OF OI TYPESType Inheritanc
eSeverity Fractures Bone
DeformityStature DI Sclerae Hearing
LossI* AD Mild Few to 100 Uncommo
nNormal to short
Rare Blue 50%
II AD Perinatal Lethal
Multiple fractures of ribs, compression of long bones
Severe Severely short
Yes Dark Blue
-
III AD (rare recessive)
Severe Thin gracile bones, many fractures, popcorn epiphyses
Moderate to Severe
Very short
Yes Blue Frequent
IV* AD Moderate to Mild
Multiple Mild to Moderate
Variably short
Varies Normal to Grey
Some
V AD Moderate Multiple w/ hypertrophic fractures
Moderate Variable No Normal No
VI Uncertain Moderate Multiple Rhizomelic Shortening
Mildly short
No Normal No
VII AR Moderate Multiple Yes Mildly short
No Normal No
TREATMENTS Management of fractures: short-term,
lightweight casts/splints/braces PT and/or OT Safe physical activity: swimming, walking,
stationary cycling Rodding (esp. children) Reconstructive surgery, joint replacements
THERAPIES UNDER INVESTIGATION Bisphosphonates (Pamidronate)
Decrease bone resorption to increase bone mass and strength
Mostly in severe types Human growth hormone
Appears to improve linear growth rates and bone formation
Bone marrow transplant Mesenchymal stem cells differentiate into normal
osteoblasts
LITERATURE CITED Genetic Home Reference. Dentinogenesis
Imperfecta. Reviewed November 2009. Retrieved from < http://ghr.nlm.nih.gov/condition/dentinogenesis-imperfecta>
Steiner, R.D., MD; M.G. Pepsin, MS, CGC; P.H. Byers, MD. Posted 28 January 2005. Osteogenesis Imperfecta: Brittle Bone Disease, OI. Retrieved from <https://ecampus.wvu.edu/webct/urw/tp3175580449031.lc3171995902051/displayURLForQM.dowebct?URLId=3175580617031&resetBreadcrumb=false&displayBCInsideFrame=true>