FKBP10 – Osteogenesis imperfecta Type XI

Osteogenesis imperfecta Type XI is an autosomal recessive bone fragility disorder caused by biallelic variants in the FKBP10 gene, which encodes the ER-localized chaperone FKBP65. Affected individuals present with early-onset fractures and progressive skeletal deformities linked to defective collagen processing. Inheritance follows an autosomal recessive pattern with concordant segregation in multiple unrelated families.

To date, 37 probands have been reported with FKBP10-related OI Type XI: 19 probands in 16 families (PMID:34173012), 15 patients (PMID:38927610), and 3 patients from a consanguineous pedigree (PMID:36655627). This body of evidence supports a Strong gene–disease association.

The variant spectrum encompasses 17 distinct alleles, predominantly protein-truncating changes. Notable variants include c.1490G>A (p.Trp497Ter) and c.831dup (p.Gly278ArgfsTer21), with c.1490G>A observed recurrently in unrelated patients, suggesting founder effects. Missense and splice-site variants also contribute to disease.

Functional studies corroborate a loss-of-function mechanism: FKBP65 undergoes rapid proteasome-dependent proteolysis under ER stress, leading to deficient collagen folding (PMID:21761186). In murine Fkbp10-null fibroblasts, reconstitution with wild-type FKBP65—but not PPIase-deficient mutants—restores hydroxylysine-aldehyde derived collagen cross-links (PMID:28378777), confirming mechanistic concordance with human phenotype.

Clinically, patients exhibit bone fragility (HP:0002755), skeletal deformities (HP:0002653), and scoliosis (HP:0002650). Bisphosphonate therapy increases lumbar spine bone mineral density Z-scores and reduces fracture rates in OI Type XI, although long-term skeletal deformities may progress despite treatment.

Integration of genetic and functional data yields a Strong association of FKBP10 with Osteogenesis imperfecta Type XI. Key Take-home: FKBP10 should be included on diagnostic gene panels for autosomal recessive OI, guiding therapeutic decisions and prognostic counseling.

References

• Calcified tissue international • 2021 • Long-Term Follow-Up Outcomes of 19 Patients with Osteogenesis Imperfecta Type XI and Bruck Syndrome Type I Caused by FKBP10 Variants. PMID:34173012
• Genes • 2024 • Presentation of Rare Phenotypes Associated with the FKBP10 Gene. PMID:38927610
• Molecular genetics & genomic medicine • 2023 • Clinical features and molecular characterization of Chinese patients with FKBP10 variants. PMID:36655627
• 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
• 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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