COX10 – Cytochrome-c Oxidase Deficiency Disease

Cytochrome-c oxidase deficiency disease is an autosomal recessive mitochondrial disorder caused by impaired assembly of Complex IV. The nuclear gene COX10 encodes heme A:farnesyltransferase, catalyzing the first step in heme A biosynthesis essential for cytochrome c oxidase function. Biallelic COX10 variants disrupt enzyme assembly, leading to early-onset multisystem phenotypes in Cytochrome-c Oxidase Deficiency Disease.

Initial evidence arose from a consanguineous pedigree with isolated Complex IV deficiency linked to chromosome 17p13.1–q11.1, in which homozygous c.611A>G (p.Asn204Ser) segregated with disease in multiple affected siblings (PMID:10767350). This confirmed autosomal recessive inheritance and familial segregation.

Subsequent case series identified two unrelated probands presenting with anemia, Leigh syndrome, sensorineural deafness and hypertrophic cardiomyopathy who carried four different missense alleles (c.587C>A (p.Thr196Lys), c.674C>T (p.Pro225Leu), c.1007A>G (p.Asp336Gly), c.1007A>T (p.Asp336Val)) in compound or homozygous states (PMID:12928484). These findings expanded the phenotypic spectrum and variant diversity.

A separate pediatric report described a 3-year-old with developmental regression and muscle weakness harboring homozygous c.1130C>T (p.Thr377Ile) (PMID:38846886). An adult-onset case demonstrated compound heterozygosity for c.1007A>T (p.Asp336Val) and c.1015C>T (p.Arg339Trp), confirming COX10 involvement in milder, late-onset presentations (PMID:24100867).

Functional studies have substantiated COX10 pathogenicity. A patient fibroblast line with a start-codon mutation c.2T>C (p.Met1Thr) showed reduced assembly of COX subunits I–IV and rescue upon COX10 overexpression (PMID:15455402). In vitro expression of an alternative oxidase from Ciona intestinalis compensated for COX deficiency in COX10-silenced cells, restoring growth and oxidative stress resistance (PMID:20049701).

Collectively, five independent probands from four families with biallelic COX10 mutations, autosomal recessive segregation, and concordant functional rescue establish a strong gene–disease relationship. This evidence supports molecular diagnosis, carrier screening, and targeted therapeutic development for COX10-related cytochrome-c oxidase deficiency.

References

• Human molecular genetics • 2000 • A mutation in the human heme A:farnesyltransferase gene (COX10) causes cytochrome c oxidase deficiency. [PMID:10767350]
• Human molecular genetics • 2003 • Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency. [PMID:12928484]
• Annals of medicine and surgery • 2012 • Complex mitochondrial disease caused by the mutation of COX10 in a toddler: a case-report study. [PMID:38846886]
• JAMA neurology • 2013 • COX10 mutations resulting in complex multisystem mitochondrial disease that remains stable into adulthood. [PMID:24100867]
• Annals of neurology • 2004 • Cytochrome c oxidase biogenesis in a patient with a mutation in COX10 gene. [PMID:15455402]
• EMBO molecular medicine • 2009 • Expression of the alternative oxidase complements cytochrome c oxidase deficiency in human cells. [PMID:20049701]

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