Mutations in the Gene Encoding the RER Protein FKBP65 Cause Autosomal-Recessive Osteogenesis Imperfecta

• DOI: 10.1016/j.ajhg.2010.02.022
• Publication Date: 2010-04-02T04:25:09Z
• Authors: Yasemin Alanay; Hrispima Avaygan; Natalia Camacho; G. Eda Utine; Koray Boduroglu; Dilek Aktas; Mehmet Alikasifoglu; Ergul Tuncbilek; Diclehan Orhan; Filiz Tiker Bakar; Bernard Zabel; Andrea Superti-Furga; Leena Bruckner-Tu...; Cindy J.R. Curry; Shawna Pyott; Peter H. Byers; David R. Eyre; Dustin Baldridge; Brendan Lee; Amy E. Merrill; Elaine C. Davis; Daniel H. Cohn; Nurten Akarsu; Deborah Krakow
• Keywords: Procollagen peptidase; Type I collagen

Osteogenesis imperfecta is a clinically and genetically heterogeneous brittle bone disorder that results from defects in the synthesis, structure, or posttranslational modification of type I procollagen. Dominant forms of OI result from mutations in COL1A1 or COL1A2, which encode the chains of the type I procollagen heterotrimer. The mildest form of OI typically results from diminished synthesis of structurally normal type I procollagen, whereas moderately severe to lethal forms of OI usually result from structural defects in one of the type I procollagen chains. Recessively inherited OI, usually phenotypically severe, has recently been shown to result from defects in the prolyl-3-hydroxylase complex that lead to the absence of a single 3-hydroxyproline at residue 986 of the alpha1(I) triple helical domain. We studied a cohort of five consanguineous Turkish families, originating from the Black Sea region of Turkey, with moderately severe recessively inherited OI and identified a novel locus for OI on chromosome 17. In these families, and in a Mexican-American family, homozygosity for mutations in FKBP10, which encodes FKBP65, a chaperone that participates in type I procollagen folding, was identified. Further, we determined that FKBP10 mutations affect type I procollagen secretion. These findings identify a previously unrecognized mechanism in the pathogenesis of OI.