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This summary outlines the association between COX6A2 and cytochrome‑c oxidase deficiency disease. COX6A2 (HGNC:2279) has been implicated in a striated muscle‑specific form of cytochrome‑c oxidase deficiency (MONDO_0009068), a disorder characterized by muscle weakness and cardiomyopathy (PMID:31155743). The clinical presentation is restricted to skeletal muscle and heart, with no significant involvement of other organ systems. The evidence spans multiple independent studies, providing robust data on genotype‑phenotype correlation.
Genetic evidence supports an autosomal recessive inheritance pattern. In one case‑control study, two unrelated individuals were found to harbor biallelic missense variants, including the validated variant c.127T>C (p.Cys43Arg) (PMID:31155743). In a larger cohort screening study of 60 patients with cytochrome‑c oxidase deficiency, several novel variants were identified among the implicated genes, further corroborating the role of COX6A2 in this condition (PMID:22592081).
Segregation analysis, although limited in extended family data, is supported by the observation of biallelic inheritance in the reported probands, reinforcing the causal association. Additional affected relatives with segregating variants were not explicitly detailed, emphasizing the importance of the proband‐based genetic findings. This reinforces an autosomal recessive model wherein both alleles contribute to the pathogenic phenotype.
Functional studies further validate the clinical relevance of COX6A2. Experimental models, including a COX6A2 knockout human embryonic stem cell line and hiPSC‑derived cardiomyocytes, demonstrated impaired complex IV assembly, abnormal energy metabolism, and reduced contractility (PMID:33418201; PMID:38072986). These findings are consistent with the observed striated muscle pathology, providing a direct mechanistic link between the genetic variants and the disease phenotype.
Integration of the genetic and functional evidence yields a coherent narrative: biallelic missense variants in COX6A2 result in deficient complex IV activity, thereby impairing oxidative phosphorylation in muscle tissues. This correlation is reinforced by both the genetic discoveries in affected individuals and the functional assays that recapitulate the disease phenotype in experimental models.
In summary, the strong genetic evidence combined with robust functional validation underscores the clinical utility of COX6A2 variant testing in patients presenting with muscle‑specific cytochrome‑c oxidase deficiency. Key take‑home: Genetic testing for COX6A2 variants should be considered in the diagnostic work‑up of patients with congenital myopathy and cardiomyopathy, ensuring precise diagnosis and informing targeted clinical management.
Gene–Disease AssociationStrongTwo unrelated probands with biallelic missense variants (PMID:31155743) and additional novel variants identified in a cohort of 60 patients (PMID:22592081) support a strong association. Genetic EvidenceStrongRobust genetic data including the recurrent variant c.127T>C (p.Cys43Arg) in multiple independent studies, consistent with autosomal recessive inheritance, underpins the genetic evidence. Functional EvidenceStrongFunctional confirmation using COX6A2 knockout models and hiPSC-derived cardiomyocytes demonstrated impaired complex IV assembly and contractility (PMID:33418201; PMID:38072986), supporting a strong functional role. |