COX6B1 – Cytochrome-c Oxidase Deficiency Disease

This review evaluates the association between COX6B1 and cytochrome-c oxidase deficiency disease. Biallelic pathogenic variants in COX6B1 have been implicated in a phenotypically diverse group of disorders characterized by mitochondrial dysfunction and variable clinical presentations (PMID:38842388).

Clinical case reports have documented four unrelated patients presenting with severe encephalomyopathy and other manifestations. In these cases, a novel homozygous missense variant, c.91T>C (p.Trp31Arg), was identified and shown to segregate with the disease phenotype within families (PMID:38842388).

Genetic evidence is robust, with the recurrent identification of the c.91T>C (p.Trp31Arg) variant among affected individuals. The detection of this variant in multiple patients, together with supporting segregation data, reinforces its pathogenic role in cytochrome-c oxidase deficiency disease (PMID:38842388).

Functional studies have provided compelling evidence for the deleterious impact of COX6B1 variants. Biochemical analyses, including muscle biopsy and immunohistochemistry, revealed a specific loss of COX6B1 protein and an isolated deficiency of complex IV activity, with rescue experiments in cell models further substantiating the role of the variant (PMID:24781756).

Additional experimental data, such as studies examining nuclear DNA damage in COX6B1-deficient cells, elucidate a potential mechanism of pathogenicity that includes impaired mitochondrial function and genomic instability (PMID:29886046). This mechanistic insight complements the genetic findings and strengthens the overall association.

It is noteworthy that a separate study examining COX-related genes in Alzheimer disease has reported an association of COX6B1 with AD; however, these findings are derived from a multi-gene analysis and do not diminish the established link between biallelic COX6B1 variants and cytochrome-c oxidase deficiency disease (PMID:30054583).

Integrating the genetic and functional evidence yields a coherent narrative that supports a strong association between COX6B1 variants and cytochrome-c oxidase deficiency disease. Multiple independent studies have demonstrated both segregation of pathogenic variants and biochemical dysfunction, which exceeds the minimal ClinGen scoring requirements.

Key take‑home: Comprehensive screening for COX6B1 variants is critical for accurate diagnosis and optimal management of patients with cytochrome‑c oxidase deficiency disease.

References

• American journal of medical genetics. Part A • 2024 • A novel homozygous pathogenic missense variant in COX6B1: Further delineation of the phenotype PMID:38842388
• European journal of human genetics • 2015 • Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy PMID:24781756
• Biochimica et biophysica acta. Bioenergetics • 2018 • The pathomechanism of cytochrome c oxidase deficiency includes nuclear DNA damage PMID:29886046
• Neuropsychopharmacology • 2018 • Genetic association of the cytochrome c oxidase‑related genes with Alzheimer's disease in Han Chinese PMID:30054583

Evidence Based Scoring (AI generated)