Mutations In The Gene Encoding The Rer Protein Fkbp65 Cause Autosomal-Recessive Osteogenesis Imperfecta
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Tarih
2010Yazar
Alanay, Yasemin
Avaygan, Hrispima
Camacho, Natalia
Utine, G. Eda
Boduroglu, Koray
Aktas, Dilek
Alikasifoglu, Mehmet
Tuncbilek, Ergul
Orhan, Diclehan
Bakar, Filiz Tiker
Zabel, Bernard
Superti-Furga, Andrea
Bruckner-Tuderman, Leena
Curry, Cindy J. R.
Pyott, Shawna
Byers, Peter H.
Eyre, David R.
Baldridge, Dustin
Lee, Brendan
Merrill, Amy E.
Davis, Elaine C.
Cohn, Daniel H.
Akarsu, Nurten
Krakow, Deborah
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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 1 procollagen, whereas moderately severe to lethal forms of OI usually result from structural defects in one of the type 1 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 alpha 1 (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 1 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.