Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 86, Issue 3, Pages 389-398Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2010.01.034
Keywords
-
Categories
Funding
- NIH [1 F31 AG032825-01, AR051582]
- HHMI Molecular Medicine Program
- Osteogenesis Imperfecta Foundation, Inc.
- Freudmann Fund at the University of Washington
Ask authors/readers for more resources
Osteogenesis imperfecta (OI) is characterized by bone fragility and fractures that may be accompanied by bone deformity, dentinogenesis imperfecta, short stature, and shortened life span. About 90% of individuals with 01 have dominant mutations in the type I collagen genes COL1A1 and COL1A2. Recessive forms of OI resulting from Mutations in collagen-modifying enzymes and chaperones CRTAP, LEPRE1, PPIB, and FKBP10 have recently been identified. We have identified an autosomal-recessive missense mutation (c.233T>C, pLeu78Pro) in SERPINH1, which encodes the collagen chaperone-like protein HSP47, that leads to a severe 01 phenotype. The mutation results in degradation of the endoplasmic reticulum resident HSP47 via the proteasome. Type 1 procollagen accumulates in the Golgi of fibroblasts from the affected individual and a population of the secreted type I procollagen is protease sensitive. These findings suggest that HSP47 monitors the integrity of the triple helix of type I procollagen at the ER/cis-Golgi boundary and, when absent, the rate of transit from the ER to the Golgi is increased and helical structure is compromised. The normal 3-hydroxylation of the prolyl residue at position 986 of the triple helical domain of pro alpha 1(1) chains places the role of HSP47 downstream from the CRTAP/P3H1/CyPB complex that is involved in prolyl 3-hydroxylation. Identification of this mutation in SERPINH1 gives further insight into critical steps of the collagen biosynthetic pathway and the molecular pathogenesis of OI.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available