FKBP10 – Osteogenesis Imperfecta

FKBP10 encodes the endoplasmic reticulum chaperone FKBP65, which assists folding and cross-linking of type I procollagen. Osteogenesis imperfecta (OI) is a heritable disorder of bone fragility and osteopenia characterized by recurrent fractures, short stature, and deformities (MONDO:0019019). While dominant OI is typically caused by collagen I gene mutations, autosomal recessive forms arise from defects in collagen‐modifying proteins including FKBP10 (PMID:20839288).

Autosomal recessive FKBP10 mutations have been reported in multiple unrelated cohorts, manifesting as OI type XI or Bruck syndrome with or without congenital contractures. In the inaugural study, five families with biallelic FKBP10 variants exhibited bone fragility and contractures, consistent with a recessive inheritance pattern (PMID:20839288). Subsequent reports described individual probands harboring homozygous splicing (c.1399+1G>A) (PMID:22061863), frameshift (c.976del) (PMID:27362741), and splice‐acceptor (c.1257-2A>G) mutations (PMID:29801479).

A large cohort study further delineated 38 affected individuals from 21 families with FKBP10 variants, all demonstrating autosomal recessive segregation and clinical features of OI, with additional 5 unique probands in separate reports, totaling 43 individuals (PMID:22949511). Segregation analysis confirmed variant‐phenotype co‐segregation in consanguineous pedigrees (at least 19 additional affected relatives) and a spectrum of loss‐of‐function alleles including nonsense, frameshift, and splice site changes. A representative variant is c.612C>G (p.Tyr204Ter).

Functional studies demonstrate that FKBP65 deficiency disrupts collagen telopeptide lysine hydroxylation and intermolecular cross-link formation. In FKBP10-null murine fibroblasts, loss of FKBP65 leads to a marked reduction in hydroxylysine-aldehyde derived collagen cross-links and accumulation of non-hydroxylated cross-links, phenocopying PLOD2 deficiency (PMID:28378777). These findings establish a loss-of-function mechanism via impaired collagen maturation.

No studies have reported compelling evidence refuting the association. The consistency of genetic findings and concordant functional data across multiple models underscore a robust gene-disease link.

In summary, autosomal recessive FKBP10 mutations cause OI type XI through loss of chaperone function for type I collagen, leading to bone fragility and deformities. FKBP10 sequencing is recommended in patients with recessive OI phenotypes, particularly those without collagen I mutations.

Key Take-home: FKBP10 is a validated recessive OI gene; loss-of-function variants impair collagen cross-linking and should be included in diagnostic gene panels for osteogenesis imperfecta.

References

• Journal of bone and mineral research • 2011 • Mutations in FKBP10 cause recessive osteogenesis imperfecta and Bruck syndrome. PMID:20839288
• Human molecular genetics • 2013 • Mutations in FKBP10, which result in Bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen. PMID:22949511
• Scientific reports • 2017 • FKBP65-dependent peptidyl-prolyl isomerase activity potentiates the lysyl hydroxylase 2-driven collagen cross-link switch. PMID:28378777

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