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Bruck syndrome 1 (BS1) is a rare autosomal recessive connective tissue disorder characterized by congenital joint contractures, bone fragility with onset in infancy, severe limb deformities, and progressive scoliosis. FKBP10 (FK506 binding protein 65) encodes an endoplasmic reticulum–localized peptidyl-prolyl isomerase essential for proper collagen folding and cross-linking. BS1 due to FKBP10 mutations presents with arthrogryposis multiplex congenita, recurrent fractures, short stature, spina bifida, and lower limb deformities leading to inability to walk (PMID:37422836).
Genetic analyses have identified biallelic FKBP10 variants in at least 12 unrelated probands from four consanguineous and outbred families, supporting autosomal recessive inheritance. Two siblings of Pashtun origin were homozygous for c.344G>A (p.Arg115Gln) (PMID:37422836), and a cohort of 15 patients included 10 BS1 cases carrying recurrent variants such as c.1491G>A (p.Trp497Ter) (PMID:38927610). No additional segregation beyond affected sib-pairs has been reported to date.
The variant spectrum in BS1 includes missense (e.g., p.Arg115Gln), nonsense (e.g., p.Trp497Ter), frameshift (e.g., p.Gly278ArgfsTer21), and splice-site mutations (e.g., c.918-3C>G), all predicted or shown to abolish FKBP65 function. The recurrent p.Arg115Gln and p.Trp497Ter alleles have been reported in multiple families, suggesting possible founder effects in specific populations. Deep intronic or structural variants have not yet been described in BS1.
Functional studies demonstrate a loss-of-function mechanism: FKBP65-deficient murine fibroblasts exhibit reduced hydroxylysine-aldehyde–derived collagen cross-links (HLCCs) and accumulation of non-hydroxylated cross-links, recapitulating human bone fragility (PMID:28378777). Rescue of HLCC formation by wild-type but not PPIase-inactive FKBP65 confirms the critical role of FKBP10 in collagen maturation. Additional reports in OI models show that FKBP10 truncating mutations lead to premature proteasomal degradation and impaired procollagen secretion (PMID:22107750).
No studies to date have refuted the FKBP10–BS1 association or reported significant phenotypic heterogeneity beyond the established BS1 and OI‐like continuum. While rare FKBP10 variants have been observed in other contexts (e.g., TOF), their pathogenicity in BS1 remains unchallenged.
In summary, biallelic loss-of-function variants in FKBP10 cause BS1 through a recessive mechanism involving defective collagen isomerization and cross-linking. Genetic testing for FKBP10 should be prioritized in infants with congenital contractures and early fractures. Key take-home: FKBP10 sequence analysis enables definitive diagnosis of BS1, guiding clinical management and genetic counseling.
Gene–Disease AssociationStrongAt least 12 unrelated probands in four families, consistent autosomal recessive segregation and concordant functional data Genetic EvidenceStrongTwelve probands with biallelic FKBP10 variants including homozygous and recurrent alleles Functional EvidenceModerateMurine fibroblast models and biochemical assays demonstrate loss of FKBP65 function and impaired collagen cross-linking |