Pathogenic mitochondrial mt-tRNAAla variants are uniquely associated with isolated myopathy

• DOI: 10.1038/ejhg.2015.73
• Publication Date: 2015-04-15T10:23:09Z
• Authors: Diana Lehmann; Kathrin Schubert; Pushpa R Joshi; Steven A Hardy; Helen A L Tuppen; Karen Baty; Emma L Blakely; Christian Bamberg; Stephan Zierz; Marcus Deschauer; Robert W Taylor
• Keywords: Adult; 0301 basic medicine; Base Sequence; Molecular Sequence Data; Short Report; RNA, Transfer, Ala; DNA, Mitochondrial; Electron Transport Complex IV; 03 medical and health sciences; Muscular Diseases; Mutation; Humans; Female; Aged

Pathogenic mitochondrial DNA (mtDNA) point mutations are associated with a wide range of clinical phenotypes, often involving multiple organ systems. We report two patients with isolated myopathy owing to novel mt-tRNA(Ala) variants. Muscle biopsy revealed extensive histopathological findings including cytochrome c oxidase (COX)-deficient fibres. Pyrosequencing confirmed mtDNA heteroplasmy for both mutations (m.5631G>A and m.5610G>A) whilst single-muscle fibre segregation studies (revealing statistically significant higher mutation loads in COX-deficient fibres than in COX-positive fibres), hierarchical mutation segregation within patient tissues and decreased steady-state mt-tRNA(Ala) levels all provide compelling evidence of pathogenicity. Interestingly, both patients showed very high-mutation levels in all tissues, inferring that the threshold for impairment of oxidative phosphorylation, as evidenced by COX deficiency, appears to be extremely high for these mt-tRNA(Ala) variants. Previously described mt-tRNA(Ala) mutations are also associated with a pure myopathic phenotype and demonstrate very high mtDNA heteroplasmy thresholds, inferring at least some genotype:phenotype correlation for mutations within this particular mt-tRNA gene.