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

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-Tuderman, Cindy J.R. Curry, Shawna Pyott, Peter H. Byers, David R. Eyre, Dustin Baldridge, Brendan Lee, Amy E. MerrillElaine C. Davis, Daniel H. Cohn, Nurten Akarsu, Deborah Krakow

Research output: Contribution to journalArticlepeer-review

212 Scopus citations

Abstract

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 α1(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.

Original languageEnglish
Pages (from-to)551-559
Number of pages9
JournalAmerican journal of human genetics
Volume86
Issue number4
DOIs
StatePublished - Apr 9 2010

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