FKBP10 – Arthrogryposis-like Syndrome

FKBP10 encodes the endoplasmic reticulum chaperone FKBP65, essential for type I collagen folding and telopeptide hydroxylation. Biallelic loss-of-function variants in FKBP10 cause a spectrum of recessive bone and joint disorders, including osteogenesis imperfecta and Bruck syndrome, and have been implicated in an arthrogryposis-like syndrome characterized by congenital contractures without fractures (MONDO:0015241).

Inheritance is autosomal recessive, with multiple unrelated families demonstrating segregating FKBP10 variants. A homozygous three–nucleotide in-frame deletion, c.877_879del (p.Tyr293del), was identified in Yup’ik Inuit kindreds presenting with isolated contractures (Kuskokwim syndrome) (PMID:23712425), and a novel splice-site variant, c.391+4A>T, was found in 10 affected individuals of a consanguineous Palestinian family, all exhibiting arthrogryposis-like contractures without bone fractures (PMID:32531462).

The variant spectrum includes in-frame deletions (p.Tyr293del), splice-site mutations (c.391+4A>T), and nonsense or frameshift alleles leading to absent FKBP65 protein. Recurrent alleles are seen in population isolates (3% carrier rate for p.Tyr293del) and multiple consanguineous pedigrees.

Functional studies of FKBP10-null and patient-derived fibroblasts demonstrate markedly reduced FKBP65 levels, impaired telopeptide lysine hydroxylation, and decreased hydroxylysine-aldehyde–derived collagen cross-links (HLCCs), a defect rescued by wild-type FKBP65 but not by PPIase-deficient mutants (PMID:23712425; PMID:28378777). This supports a loss-of-function mechanism underlying the contracture phenotype.

Segregation analysis across at least three distinct pedigrees accounts for >10 affected relatives with complete co-segregation of FKBP10 alleles and arthrogryposis-like manifestations, fulfilling strong genetic evidence criteria.

In summary, autosomal recessive FKBP10 variants reliably cause an arthrogryposis-like syndrome through loss of FKBP65-mediated collagen cross-linking. FKBP10 sequencing should be considered in patients with congenital joint contractures, even in the absence of fractures. Key Take-home: FKBP10 variant analysis is clinically useful for diagnosing recessive arthrogryposis-like presentations.

References

• Human mutation • 2013 • Kuskokwim syndrome, a recessive congenital contracture disorder, extends the phenotype of FKBP10 mutations. PMID:23712425
• European journal of medical genetics • 2020 • New insights on the clinical variability of FKBP10 mutations. PMID:32531462
• Scientific reports • 2017 • FKBP65-dependent peptidyl-prolyl isomerase activity potentiates the lysyl hydroxylase 2-driven collagen cross-link switch. PMID:28378777
• Genes • 2024 • Presentation of Rare Phenotypes Associated with the FKBP10 Gene. PMID:38927610

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