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In an autosomal recessive inheritance pattern, a single proband with isolated cytochrome-c oxidase deficiency disease harboured compound heterozygous variants in COA3, including c.199dup (p.Leu67ProfsTer21) and c.215A>G (p.Tyr72Cys) (PMID:25604084). The patient presented with neuropathy, exercise intolerance, obesity (HP:0001513), and short stature (HP:0004322). Blue-native PAGE of fibroblasts demonstrated near absence of complex IV assembly and pulse-labelling assays showed decreased COX1 synthesis. Retroviral expression of wild-type COA3 fully rescued COX assembly and mitochondrial translation defects, confirming pathogenicity and supporting a mechanism of disrupted COX1 stabilization via COA3–COX14 interdependence. Despite robust functional rescue, evidence is limited to a single family. Key take-home: COA3 sequencing should be considered in patients with isolated complex IV deficiency presenting with neuropathy, exercise intolerance, obesity, and short stature.
Gene–Disease AssociationLimitedSingle proband with compound heterozygous COA3 variants and supportive functional data Genetic EvidenceLimitedCompound heterozygous missense and frameshift variants in one individual ([PMID:25604084]) Functional EvidenceModerateRescue of COX assembly and translation defects in patient fibroblasts; BN-PAGE and immunoblot concordant |