title: Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta.
abstract: 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 proalpha1(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.
authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
authors.forename: Helena E
authors.initials: HE
authors.lastname: Christiansen
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schwarze
authors.forename: Shawna M
authors.initials: SM
authors.lastname: Pyott
authors.forename: Abdulrahman
authors.initials: A
authors.lastname: AlSwaid
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al Balwi
authors.forename: Shatha
authors.initials: S
authors.lastname: Alrasheed
authors.forename: Melanie G
authors.initials: MG
authors.lastname: Pepin
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Weis
authors.forename: David R
authors.initials: DR
authors.lastname: Eyre
authors.forename: Peter H
authors.initials: PH
authors.lastname: Byers
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D002675:Child, Preschool; D024042:Collagen Type I / Q000737:chemistry / Q000378:metabolism; D003241:Consanguinity; D017124:Conserved Sequence; D004247:DNA / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D017809:Fatal Outcome; D005260:Female; D005808:Genes, Recessive; D050958:HSP47 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010013:Osteogenesis Imperfecta / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D011859:Radiography; D017386:Sequence Homology, Amino Acid
chemical_list: D024042:Collagen Type I; D050958:HSP47 Heat-Shock Proteins; C494660:SERPINH1 protein, human; D004247:DNA; D046988:Proteasome Endopeptidase Complex