COX10 – Leigh Syndrome

Leigh syndrome (MONDO:0009723) is a progressive neurodegenerative disorder characterized by bilateral brainstem and basal ganglia lesions and lactic acidosis. Biallelic pathogenic variants in COX10 (Gene Symbol) disrupt heme A biosynthesis, impair cytochrome c oxidase assembly, and cause the autosomal recessive form of Leigh syndrome.

Autosomal recessive inheritance of COX10 variants has been documented in multiple unrelated probands. In a Japanese family, three siblings with spastic paraplegia and intellectual disability harbored compound heterozygous COX10 missense mutations segregating with disease (PMID:36176336). An isolated adult case of multisystem mitochondrial disease carried two deleterious missense substitutions, c.1007A>T (p.Asp336Val) and c.1015C>T (p.Arg339Trp), both confirmed as loss-of-function in yeast complementation assays (PMID:24100867). A homozygous start-codon mutation, c.2T>C (p.Met1Thr), abolished COX assembly in patient fibroblasts and was rescued by COX10 overexpression (PMID:15455402).

Pathogenic variants in COX10 include missense, initiation‐codon, and frameshift alleles. The initiation‐codon variant c.2T>C (p.Met1Thr) exemplifies a null allele preventing mitochondrial targeting. No recurrent or founder alleles have been reported to date. Clinical features commonly include neurodegeneration (HP:0002180), cardiomyopathy (HP:0001638), and exercise intolerance (HP:0003546).

Functional studies in patient cells and model organisms consistently demonstrate that COX10 loss-of-function leads to cytochrome c oxidase deficiency and defective oxidative phosphorylation. Overexpression of wild-type COX10 in deficient fibroblasts restores holoenzyme assembly, while yeast complementation and alternative oxidase (AOX) expression rescue respiratory defects.

No studies have refuted the COX10–Leigh syndrome association; phenotypic variability suggests possible genetic modifiers. Additional therapeutic evidence, such as AOX complementation, extends beyond ClinGen scoring criteria.

In summary, robust genetic and experimental data support a Strong gene–disease association for COX10 in Leigh syndrome, underpinning molecular diagnosis, genetic counseling, and potential targeted therapies.

Key Take-home: COX10 loss-of-function variants cause autosomal recessive Leigh syndrome; functional assays and model systems provide definitive diagnostic and mechanistic insights.

References

• Neurology Genetics • 2022 • Biallelic COX10 Mutations and PMP22 Deletion in a Family With Leigh Syndrome and Hereditary Neuropathy With Liability to Pressure Palsy. PMID:36176336
• 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

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