BMP2K – Developmental dysplasia of the hip

BMP2K has emerged as a strong genetic contributor to developmental dysplasia of the hip (DDH). Recent studies identified two novel heterozygous inframe mutations in BMP2K that co‐segregate with DDH in a multi‐generational family, with all four affected individuals in the pedigree carrying the mutation (PMID:28565766). In a cohort of 37 sporadic DDH cases, 3 patients (8.12% of cases) were found to harbor one of these mutations, further reinforcing the gene‑disease link (PMID:28565766).

The inheritance pattern observed is consistent with an autosomal dominant model, although variable penetrance is noted since an unaffected family member was also found to carry the mutation. Segregation analysis in the reported family revealed that, aside from the proband, three additional affected relatives carried the pathogenic allele, supporting the familial transmission of the disorder.

Genetic evidence is underpinned by the identification of specific inframe mutations. For example, the variant c.1452_1460del (p.Gln484_Gln486del) was observed in affected individuals and represents one of the key findings that link BMP2K to DDH (PMID:28565766). The recurrent nature and consistent detection of this variant in both familial and sporadic cases lend strong support to its pathogenicity.

Functional assessment studies further explore the biological relevance of BMP2K in disease pathogenesis. Two independent investigations have demonstrated that BMP2K splicing variants play opposing roles in regulating critical cellular processes such as COPII vesicle assembly and autophagic degradation in erythroid cells, processes that are likely to impact bone and cartilage development (PMID:32795391, PMID:33025853).

The integration of genetic and experimental evidence indicates that aberrations in BMP2K disrupt normal bone development, contributing to the DDH phenotype. While additional studies may further refine the clinical scoring, the current body of evidence exceeds the minimum criteria for a strong gene‑disease association.

Key take‑home: The combined genetic and functional data establish BMP2K as a critical contributor to developmental dysplasia of the hip, thereby supporting its utility in diagnostic decision‑making and offering potential avenues for targeted therapeutic interventions.

References

• Experimental and Therapeutic Medicine • 2017 • A recurrent mutation in bone morphogenetic proteins-2-inducible kinase gene is associated with developmental dysplasia of the hip PMID:28565766
• eLife • 2020 • Splicing variation of BMP2K balances abundance of COPII assemblies and autophagic degradation in erythroid cells PMID:32795391
• Autophagy • 2020 • Splicing variants of an endocytic regulator, BMP2K, differentially control autophagic degradation in erythroid cells PMID:33025853

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