Article: article from journal or magazin.
Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta.
American Journal of Human Genetics
Publication types: Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
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.
Adolescent, Case-Control Studies, Child, Cohort Studies, Collagen Type I/genetics, Female, Genes, Recessive, Homozygote, Humans, Male, Mutation/genetics, Osteogenesis Imperfecta/genetics, Osteogenesis Imperfecta/pathology, Pedigree, Phenotype, Skin/pathology, Tacrolimus Binding Proteins/genetics
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