COX10 – Mitochondrial Disease

Cytochrome c oxidase assembly factor COX10 (HGNC:2260) encodes heme A:farnesyltransferase required for the stability and activity of respiratory chain complex IV. Pathogenic autosomal recessive variants disrupt cytochrome c oxidase biogenesis, leading to multisystem mitochondrial disease (COX10; Mitochondrial Disease).

Biallelic loss-of-function variants in COX10 have been described in neonatal Leigh-like presentations. A homozygous start codon mutation c.2T>C (p.Met1Thr) abolished COX10 expression, resulting in severe cytochrome c oxidase deficiency on blue-native gels and decreased subunit levels; overexpression of wild-type COX10 in patient fibroblasts restored assembly and activity (PMID:15455402).

Compound heterozygous missense variants c.1007A>T (p.Asp336Val) and c.1015C>T (p.Arg339Trp) were reported in an adult with isolated COX deficiency manifesting as myopathy, neuropathy and multisystem involvement. Immunoblotting showed absent holoenzyme, rescue in yeast confirmed pathogenicity, and structural modeling supported destabilization of the catalytic domain (PMID:24100867).

In a cohort of 137 children with genetically defined mitochondrial disease, 21% (n=29) exhibited cardiomyopathy; one infant with a COX10 mutation died within one month of birth, linking COX10 deficiency to early cardiac failure and poor prognosis (PMID:30642647).

Complementary functional studies underscore a loss-of-function mechanism: expression of a cyanide-resistant alternative oxidase corrected growth defects and oxidative sensitivity in COX10-silenced human cells (PMID:20049701), and yeast complementation assays of 25 human COX10 variants distinguished 11 hypomorphic alleles from null alleles, correlating with cytochrome c oxidase activity and respiratory growth (PMID:39152498).

Together, these data support an autosomal recessive association between COX10 and mitochondrial disease with cardiomyopathy and Leigh-like features. Diagnostic sequencing of COX10 should be considered in suspected complex IV deficiencies. Key Take-home: COX10 loss-of-function variants cause recessive mitochondrial disease with early-onset cardiomyopathy and multisystem involvement.

References

• International journal of cardiology • 2019 • Cardiomyopathy in children with mitochondrial disease: Prognosis and genetic background. PMID:30642647
• Annals of neurology • 2004 • Cytochrome c oxidase biogenesis in a patient with a mutation in COX10 gene. PMID:15455402
• JAMA neurology • 2013 • COX10 mutations resulting in complex multisystem mitochondrial disease that remains stable into adulthood. PMID:24100867
• EMBO molecular medicine • 2009 • Expression of the alternative oxidase complements cytochrome c oxidase deficiency in human cells. PMID:20049701
• BMC research notes • 2024 • Phenotypic assessment of Cox10 variants and their implications for Leigh Syndrome. PMID:39152498

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