Abstract
Osteogenesis imperfecta (OI) is a genetic disorder of connective tissue characterized by bone fragility and alteration in synthesis and posttranslational 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, whereas Bruck syndrome type 1 has been mapped to chromosome 17, with evidence suggesting region 17p12, 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 posttranslational modification of type I procollagen, that is, 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), also has 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. Therefore, we conclude that FKBP10 mutations are a cause of recessive osteogenesis imperfecta and Bruck syndrome, possibly Bruck syndrome Type 1 since the location on chromosome 17 has not been definitely localized. © 2011 American Society for Bone and Mineral Research.
Highlights
Type I procollagen undergoes multiple intracellular and extracellular posttranslational modifications
These studies have elucidated that the peptidylprolyl cis-trans isomerase (PPIase) activity of FK506 binding protein 10 (FKBP10) functions in folding of proline-rich tropoelastin.[15]. With regard to the folding of the type I collagen heterotrimer, the activity of the FKBP10 PPIase may be marginal.[16]. In vitro, FKBP10 in conjunction with SERPINH1 has been shown to act as chaperone of the collagen heterotrimer.[17]. Further, SERPINH1 null fibroblasts have demonstrated deficient fibrillogenesis with aggregation of type I collagen in the endoplasmic reticulum (ER).[18]. Loss of the FKBP10/SERPINH1 complex owing to deletion of the SERPINH1 gene was shown originally to cause recessive osteogenesis imperfecta (OI) in a dachshund model.[19]. SERPINH1 mutations in humans had not been identified until the very recent report of a single child with the phenotype of OI type 3
In contrast to the patients with FKBP10 mutations described by Alanay and colleagues, the patients presented in these studies demonstrated a high incidence of congenital large joint contractures consistent with the diagnosis of Bruck syndrome
Summary
Type I procollagen undergoes multiple intracellular and extracellular posttranslational modifications. Previous studies have suggested that FKBP10 may have multiple innate functions, including peptidylprolyl cis-trans isomerase (PPIase) and chaperone capability These studies have elucidated that the PPIase activity of FKBP10 functions in folding of proline-rich tropoelastin.[15] With regard to the folding of the type I collagen heterotrimer, the activity of the FKBP10 PPIase may be marginal.[16] In vitro, FKBP10 in conjunction with SERPINH1 has been shown to act as chaperone of the collagen heterotrimer.[17] Further, SERPINH1 null fibroblasts have demonstrated deficient fibrillogenesis with aggregation of type I collagen in the ER.[18] Loss of the FKBP10/SERPINH1 complex owing to deletion of the SERPINH1 gene was shown originally to cause recessive OI in a dachshund model.[19] SERPINH1 mutations in humans had not been identified until the very recent report of a single child with the phenotype of OI type 3. We propose that mutations in FKBP10 may be responsible for cases of type 1 Bruck syndrome presenting with a recessive, moderately severe OI phenotype. We propose that given phenotypic variations within family members having the same genotype, Bruck syndrome type 1 may be a variant of the larger OI spectrum
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