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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Homozygosity for a Missense Mutation in SERPINH1, which Encodes the Collagen Chaperone Protein HSP47, Results in Severe Recessive Osteogenesis Imperfecta
American Journal of Human Genetics, Volume 86, No. 3, Year 2010
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Description
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 OI 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, p.Leu78Pro) in SERPINH1, which encodes the collagen chaperone-like protein HSP47, that leads to a severe OI phenotype. The mutation results in degradation of the endoplasmic reticulum resident HSP47 via the proteasome. Type I 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 proα1(I) 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. © 2010 The American Society of Human Genetics.
Authors & Co-Authors
Christiansen, Helena E.
United States, Seattle
University of Washington
Schwarze, Ulrike
United States, Seattle
University of Washington
Pyott, Shawna M.
United States, Seattle
University of Washington
Alswaid, Abdulrahman Faiz
Saudi Arabia, Riyadh
King Abdulaziz Medical City - Riyadh
Al-Balwi, Mohammed Ali
Saudi Arabia, Riyadh
King Abdulaziz Medical City - Riyadh
Alrasheed, Shatha
Saudi Arabia, Riyadh
King Abdulaziz Medical City - Riyadh
Pepin, Melanie G.
United States, Seattle
University of Washington
Weis, Mary Ann
United States, Seattle
University of Washington
Eyre, David
United States, Seattle
University of Washington
Byers, Peter H.
United States, Seattle
University of Washington
Statistics
Citations: 298
Authors: 10
Affiliations: 2
Identifiers
Doi:
10.1016/j.ajhg.2010.01.034
ISSN:
00029297
Research Areas
Cancer
Genetics And Genomics
Violence And Injury
Study Design
Cross Sectional Study