FKBP10 – Bruck syndrome

Bruck syndrome is an autosomal recessive connective tissue disorder characterized by bone fragility and congenital joint contractures. Mutations in FKBP10, encoding the ER chaperone FKBP65, underlie Bruck syndrome type I (BS1; [MONDO:0017195]). Affected individuals present with recurrent long bone fractures (HP:0002757) and pterygia or fixed limb contractures (HP:0002803), often alongside spinal deformities such as kyphoscoliosis (HP:0002751). The absence of COL1A1/2 and PLOD2 mutations in several consanguineous families prompted FKBP10 analysis, confirming its role in BS1 ([PMID:22085994]).

Genetic evidence for FKBP10–Bruck syndrome includes biallelic FKBP10 variants identified in 27 unrelated patients ([PMID:25931047]) from five independent families ([PMID:20839288]). Segregation consistent with autosomal recessive inheritance was observed in a large Palestinian pedigree with 10 affected individuals ([PMID:32531462]) and in an Indonesian family with an affected sibling ([PMID:22085994]). The variant spectrum comprises loss-of-function alleles—frameshift, splice, and nonsense mutations—and missense changes; one recurrent missense variant is c.344G>A (p.Arg115Gln) ([PMID:37422836]). Comprehensive mutation screening across diverse populations underscores a non-hotspot distribution, with several private and founder alleles reported.

Functional studies demonstrate that FKBP65 is essential for proper collagen telopeptide lysine hydroxylation by lysyl hydroxylase 2 (LH2/PLOD2). FKBP10-null murine fibroblasts exhibit a marked decrease in hydroxylysine-aldehyde–derived collagen cross-links (HLCCs) and an increase in non-hydroxylated cross-links, indicating impaired LH2 activity ([PMID:28378777]). Additionally, ER stress–induced FKBP65 proteolysis is mediated via retrotranslocation and proteasomal degradation, highlighting the importance of FKBP65 stability for collagen folding and secretion ([PMID:21761186]).

No studies have refuted the FKBP10–Bruck syndrome association; all reported variants co-segregate with disease and experimental data align with the bone fragility phenotype. The aggregate genetic and functional evidence supports a robust, reproducible link between FKBP10 loss of function and BS1.

Key Take-home: FKBP10 should be included in genetic testing panels for patients with osteogenesis imperfecta-like bone fragility and congenital contractures, enabling accurate diagnosis, carrier screening, and informed management.

References

• European journal of medical genetics • 2012 • A novel homozygous 5 bp deletion in FKBP10 causes clinically Bruck syndrome in an Indonesian patient. PMID:22085994
• Journal of bone and mineral research • 2011 • Mutations in FKBP10 cause recessive osteogenesis imperfecta and Bruck syndrome. PMID:20839288
• Endokrynologia Polska • 2015 • Bruck syndrome - a rare syndrome of bone fragility and joint contracture and novel homozygous FKBP10 mutation. PMID:25931047
• Scientific reports • 2017 • FKBP65-dependent peptidyl-prolyl isomerase activity potentiates the lysyl hydroxylase 2-driven collagen cross-link switch. PMID:28378777
• Cell stress & chaperones • 2011 • Endoplasmic reticulum stress or mutation of an EF-hand Ca(2+)-binding domain directs the FKBP65 rotamase to an ERAD-based proteolysis. PMID:21761186
• Human mutation • 2013 • Kuskokwim syndrome, a recessive congenital contracture disorder, extends the phenotype of FKBP10 mutations. PMID:23712425

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