COA8 – Mitochondrial Disease

Whole-exome sequencing identified biallelic APOPT1/COA8 mutations in two Italian sisters, a Turkish individual, and three additional unrelated children presenting severe cytochrome c oxidase (COX) deficiency with cavitating leukodystrophy on brain MRI ([PMID:25175347]). Clinical presentations ranged from infantile neurometabolic decompensation to adolescent-onset subtle neurological signs, all following a chronic, long-surviving course. A subsequent familial case of mitochondrial myopathy in two sisters harboring the homozygous c.170_173dup (p.Pro59ThrfsTer4) variant further expanded the phenotypic spectrum to include epilepsy, retinitis pigmentosa, exercise-induced muscle cramps, hearing loss, ptosis, and ragged-red fibers on muscle biopsy ([PMID:38098475]).

Autosomal recessive inheritance is supported by segregation of pathogenic variants in affected siblings (2 affected relatives). To date, at least 8 probands from 6 unrelated families have been reported, harboring primarily loss-of-function alleles (frameshift, nonsense, splice-site) and rare missense changes. The variant spectrum includes c.357dup (p.Lys120Ter) and c.218del (p.Pro73fs) among others. Functional concordance across models strengthens the causal link: APOPT1/COA8 knockout mice exhibit impaired motor coordination and reduced COX activity, while patient fibroblasts show diminished COX holocomplex and elevated reactive oxygen species that are rescued by wild-type cDNA expression ([PMID:30552096], [PMID:25175347]).

Drosophila melanogaster knockdown of the COA8 ortholog recapitulates locomotor defects, neuromuscular impairment, COX deficiency, and reduced oxidative stress resistance, underscoring a conserved role in COX assembly and protection against oxidative damage ([PMID:31555154]). Mechanistically, APOPT1/COA8 is transiently stabilized under oxidative challenge and regulated by the ubiquitin-proteasome system, aligning with observed COX holoenzyme instability in patient cells. No conflicting evidence has been reported to date.

In summary, biallelic loss-of-function variants in COA8 cause autosomal recessive mitochondrial disease characterized by isolated COX deficiency and cavitating leukoencephalopathy. Genetic testing of COA8 should be considered in patients with early-onset leukoencephalopathy and unexplained COX deficiency. This association is supported by 8 probands across 6 families, segregation data, and robust functional studies in cellular and animal models.

References

• American journal of human genetics • 2014 • Mutations in APOPT1, encoding a mitochondrial protein, cause cavitating leukoencephalopathy with cytochrome c oxidase deficiency. PMID:25175347
• EMBO molecular medicine • 2019 • APOPT1/COA8 assists COX assembly and is oppositely regulated by UPS and ROS. PMID:30552096
• Frontiers in physiology • 2019 • Knockdown of APOPT1/COA8 Causes Cytochrome c Oxidase Deficiency, Neuromuscular Impairment, and Reduced Resistance to Oxidative Stress in Drosophila melanogaster. PMID:31555154
• Frontiers in genetics • 2023 • Prominent muscle involvement in a familial form of mitochondrial disease due to a COA8 variant. PMID:38098475

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