FKBP10 – Osteogenesis Imperfecta Type III

Autosomal recessive loss-of-function variants in FKBP10 underlie Osteogenesis Imperfecta Type III, a severe bone dysplasia characterized by recurrent fractures, progressive skeletal deformities, and normal collagen type I gene sequencing. The inheritance is autosomal recessive with evidence of familial segregation in consanguineous pedigrees and a founder frameshift allele in multiple affected individuals.

In a single consanguineous Indonesian family, a homozygous 5 bp deletion in FKBP10 was identified in two affected siblings presenting with bone fragility and joint contractures, initially misdiagnosed as OI type III (1 proband’s sibling) (PMID:22085994). A larger study of 91 South African OI type III patients found FKBP10 mutations in 41 individuals (45.1%), including 35 homozygous carriers of a c.831dupC founder variant (PMID:28492130).

The variant spectrum comprises predominantly frameshift and nonsense alleles: the recurrent c.831dupC (p.Gly278ArgfsTer21) founder mutation in 35 individuals, and additional compound heterozygous and splice-site variants (e.g., c.1621C>T (p.Gln541Ter)) across diverse populations. These variants result in truncated FKBP65, predicted to abolish PPIase function and collagen chaperoning.

Functional studies demonstrate that FKBP65 deficiency in murine Fkbp10-null embryonic fibroblasts leads to a marked decrease in hydroxylysine-aldehyde–derived collagen cross-links (HLCCs) and a reciprocal increase in non-hydroxylated cross-links; reconstitution with wild-type FKBP65—but not PPIase-inactive mutants—restores normal HLCC/LCC ratios (PMID:28378777). Patient-derived cells harboring stop-gain FKBP10 alleles exhibit ER stress, reduced FKBP65 levels, and aberrant collagen alignment, confirming loss of chaperone function (PMID:22107750).

No studies have reported conflicting evidence against FKBP10 involvement in OI type III. The combined genetic and experimental data support a haploinsufficiency/dominant loss-of-function mechanism, consistent across multiple unrelated families.

Clinically, FKBP10 sequencing should be included in diagnostic panels for OI type III, particularly in populations with known founder mutations. FKBP10 genotyping enables accurate prognosis, genetic counseling, and consideration of therapeutic strategies targeting collagen cross-linking pathways.

Key take-home: Biallelic FKBP10 variants cause autosomal recessive OI type III through FKBP65 loss of PPIase activity and defective collagen cross-linking, providing a definitive genetic diagnosis and informing clinical management.

References

• South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde • 2017 • Osteogenesis imperfecta type 3 in South Africa: Causative mutations in FKBP10. PMID:28492130
• European journal of medical genetics • 2012 • A novel homozygous 5 bp deletion in FKBP10 causes clinically Bruck syndrome in an Indonesian patient. PMID:22085994
• Scientific reports • 2017 • FKBP65-dependent peptidyl-prolyl isomerase activity potentiates the lysyl hydroxylase 2-driven collagen cross-link switch. PMID:28378777
• BMC medical genetics • 2011 • Mutations in FKBP10 can cause a severe form of isolated Osteogenesis imperfecta. PMID:22107750

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