Mutations in FKBP10 cause recessive osteogenesis imperfecta and bruck syndrome.

Osteogenesis imperfecta (OI) is a genetic disorder of connective tissue characterized by bone fragility and alteration in synthesis and post-translational modification of type I collagen. Autosomal dominant OI is caused by mutations in the genes (COL1A1 or COL1A2) encoding the chains of type I collagen. Bruck syndrome is a recessive disorder featuring congenital contractures in addition to bone fragility; Bruck syndrome type 2 is caused by mutations in PLOD2 encoding collagen lysyl hydroxylase, while Bruck Syndrome type 1 has been mapped to 17q12 but the gene has remained elusive so far. Recently, the molecular spectrum of OI has been expanded with the description of the basis of a unique post-translational modification of type I procollagen, i.e. 3-prolyl-hydroxylation. Three proteins, cartilage-associated protein (CRTAP), prolyl-3-hydroxylase-1 (P3H1, encoded by the LEPRE1 gene), and the prolyl cis-trans isomerase cyclophilin-B (PPIB) form a complex that is required for fibrillar collagen 3-prolyl-hydroxylation and mutations in each gene have been shown to cause recessive forms of OI. Since then, an additional putative collagen chaperone complex, composed of FKBP10 (also known as FKBP65) and SERPINH1 (also known as HSP47), has also been shown to be mutated in recessive OI. Here, we describe five families with OI-like bone fragility in association with congenital contractures who all had FKBP10 mutations. Given the previous mapping of Bruck syndrome type 1 to the chromosomal region containing FKBP10, we conclude that FKBP10 mutations are the cause of Bruck syndrome type 1. (c) 2010 American Society for Bone and Mineral Research.