Rare monogenic disorders often exhibit significant phenotypic variability among individuals sharing identical genetic mutations. Bruck syndrome (BS), a prime example, is characterized by bone fragility and congenital contractures, although with a pronounced variability among family members. BS arises from recessive biallelic mutations in FKBP10 or PLOD2. FKBP65, the protein encoded by FKBP10, collaborates with the LH2 enzyme (PLOD2) in type I collagen telopeptide lysine hydroxylation, crucial for collagen cross-linking. To identify potential modifier genes and to investigate the mechanistic role of FKBP10 in BS pathogenesis, we established an fkbp10a knockout zebrafish model. Mass-spectrometry analysis in fkbp10a-/- mutants revealed a generally decreased type I collagen lysyl hydroxylation, paralleled by a wide skeletal variability similar to human patients. Ultrastructural examination of the skeleton in severely affected mutants showed enlarged type I collagen fibrils and disturbed elastin layers. Whole-exome sequencing of 7 mildly and 7 severely affected mutant zebrafish siblings, followed by single nucleotide polymorphism-based linkage analysis, indicated a linked region on chromosome 13, which segregates with phenotypic severity. Transcriptome analysis identified 6 differentially expressed genes (DEGs) between mildly and severely affected mutants. The convergence of genes within the linked region and DEGs highlighted bmpr1aa as a potential modifier gene, as its reduced expression correlates with increased skeletal severity. In summary, our study provides deeper insights into the role of FKBP10 in BS pathogenesis. Additionally, we identified a pivotal gene that influences phenotypic severity in a zebrafish model of BS. These findings hold promise for novel treatments in the field of bone diseases.

Bmpr1aa modulates the severity of the skeletal phenotype in an fkbp10-deficient Bruck syndrome zebrafish model