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ATP5MK encodes a small supernumerary subunit of mitochondrial ATP synthase that is essential for dimer formation and optimal ATP production. Biallelic mutations in ATP5MK have been linked to autosomal recessive Leigh syndrome, a severe pediatric mitochondrial encephalopathy characterized by psychomotor regression and necrotizing lesions in deep grey matter.
Genetic studies uncovered a recurrent homozygous splice-site variant, c.87+1G>C, in four unrelated Ashkenazi Jewish probands with Leigh syndrome (PMID:29917077). A separate sporadic case carrying a pathogenic ATP5MK mutation further corroborates this association (PMID:30240627).
Inheritance is autosomal recessive, with all affected individuals harboring biallelic c.87+1G>C variants and parents confirmed as heterozygous carriers. No additional segregation beyond the initial probands has been described, consistent with recessive transmission.
Functional assays in patient-derived fibroblasts demonstrated near-complete loss of ATP synthase dimers and severely impaired ATP synthesis, and in situ cryoelectron tomography revealed profound disturbances of mitochondrial crista ultrastructure (PMID:30240627). Rescue of ATP synthase dimerization and ATP production by wild-type ATP5MK cDNA in proband cells confirms pathogenicity (PMID:29917077).
Taken together, multiple unrelated probands with concordant biallelic splice-site mutations, consistent autosomal recessive segregation, and robust functional rescue experiments support a Strong ClinGen gene–disease association. Inclusion of ATP5MK in diagnostic panels for Leigh syndrome will facilitate early molecular diagnosis and inform potential therapeutic strategies.
Gene–Disease AssociationStrong5 probands (4 homozygous c.87+1G>C splice-site mutations) across four unrelated families ([PMID:29917077]; 1 case report [PMID:30240627]), autosomal recessive segregation and concordant functional data Genetic EvidenceStrongRecurrent homozygous c.87+1G>C identified in 4 unrelated Ashkenazi Jewish subjects; additional case report; segregation consistent with autosomal recessive inheritance Functional EvidenceModeratePatient fibroblasts show loss of ATP synthase dimers and disrupted cristae by cryo-ET; wild-type ATP5MK cDNA rescue restores dimerization and ATP synthesis |