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.
Keywords: Bruck syndrome; modifier genes; phenotypic variability; skeletal disease; zebrafish models.
Phenotypic variability among siblings with identical genetic mutations hints at the involvement of modifier genes. Here, we established and investigated an fkbp10a knockout zebrafish model for Bruck syndrome type I, which reflects skeletal variability in human patients. Through comprehensive analysis, bmpr1aa emerged as a putative modifier gene, demonstrating significant correlations with disease severity. This investigation provides a new approach for identifying modifier genes implicated in skeletal disorders and extends its applicability to other rare diseases with variable phenotypes. Furthermore, this study improves our understanding of FKBP10 gene function and offers new insights into potential therapeutic strategies targeting modifier genes in affected human populations. Such interventions hold considerable promise for preventing, ameliorating, or potentially reversing disease phenotypes in genetically predisposed individuals.
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