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Phenotype, OI Type II, Bone Structure and Function, Initial Studies | BIOEN 588, Study notes of Biology
Pathogenesis Material Type: Notes; Class: BIOEN PRINC PHYS; Subject: Bioengineering; University: University of Washington - Seattle; Term: Unknown 1989;
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Post-mortem photo
Post-mortem x-ray image
Phenotype, OI type II
Bone structure & function
Human femur
A decalcified bone
Post-mortem x-ray
OI type II
OSTEOGENESIS IMPERFECTA
Definition Clinical syndromes Demographics Prominent phenotype
- bone weakness
- abnormal mineralization Likely candidate for mutation? Type I collagen! Post-mortem x-rays, OI type II
Collagen structure & biosynthesis / biomineralization
Structure
Biosynthesis
Initial Studies
Penttinen, R.P., Lichtenstein, J.R., Martin, G.R., and McKusick, V.A. (1975) Abnormal collagen metabolism in cultured cells in osteogenesis imperfecta. Proc Natl Acad Sci U S A 72:586. Barsh, G.S., and Byers, P.H.(1981) Reduced secretion of structurally abnormal type I procollagen in a form of osteogenesis imperfecta. Proc Natl Acad Sci U S A 78:5142. Barsh, G.S., David, K.E., and Byers, PH. (1982) Type I osteogenesis imperfecta: a nonfunctional allele for pro alpha 1 (I) chains of type I procollagen. Proc Natl Acad Sci U S A 79:3838. Chu, M.L., Williams, C.J., Pepe, G., Hirsch, J.L., Prockop, D.J., Ramirez, F. (1983) Internal deletion in a collagen gene in a perinatal lethal form of osteogenesis imperfecta. Nature 304:78.
G A T C G A T C
Gly Asp
Glycine mutations are the most common structural mutations
Gly - X - Y - Gly - X - Y
Ala, Asp, Arg, Ser, Cyc, Trp, Val, Tyr, Term
Gly Gly Gly (^) Gly Gly Asp
Normal Abnormal
Inheritance patterns
New Accident
OI IV
OI II
Inheritance patterns
Somatic Mosaicism
OI II OI II
Inheritance patterns
Gonadal Mosaicism
?
Transmission electron micrograph
Procollagen Structure C OI OI OI OI
Protease Assay
Hypothesis
Cellular Pathology Based on Abnormal Procollagen Structure-Function
Abnormal procollagen is retained inside
of OI fibroblasts.
X
Chromosome 17 7
New Accident
Why does mutant collagen
accumulate in the
endoplasmic reticulum of OI
fibroblasts?
What is a dominant negative
mutation?
Transmission electron micrograph