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Mitochondrial cytochrome c oxidase subunit III (COX3) is encoded by MT-CO3 and is critical for complex IV function. Only a single family with Leigh syndrome harbored the m.9541T>C coding variant in MT-CO3 alongside the pathogenic m.1555A>G mutation in MT-RNR1; the COX3 change was demonstrated to be non-contributory to hearing impairment and LS phenotype (1 proband, no segregation) (PMID:32867169). No unrelated probands with causative MT-CO3 variants have been reported.
Functional studies in yeast and mammalian models confirm that COX3 is indispensable for complex IV assembly and activity, but no assays to date have directly linked MT-CO3 sequence alterations to the Leigh syndrome phenotype. By contrast, LS-associated complex IV deficiencies are typically driven by mutations in other mitochondrial subunits or nuclear assembly factors. Key take-home: current genetic and experimental evidence does not support diagnostic utility of MT-CO3 sequencing in Leigh syndrome.
Gene–Disease AssociationLimitedNo unrelated probands with pathogenic MT-CO3 variants in Leigh syndrome; single report of m.9541T>C deemed non-contributory to phenotype Genetic EvidenceLimitedNo pathogenic MT-CO3 coding variants reported in LS patients; m.9541T>C variant shown non-contributory in one pedigree ([PMID:32867169]) Functional EvidenceLimitedFunctional studies demonstrate COX3 role in complex IV biogenesis but none directly assess MT-CO3 variants in Leigh syndrome |