期刊
EUROPEAN JOURNAL OF HUMAN GENETICS
卷 23, 期 12, 页码 1735-1738出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ejhg.2015.73
关键词
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资金
- German Ministry of Education and Research
- Wellcome Trust [096919Z/11/Z]
- Medical Research Council (UK) Centre for Translational Muscle Disease Research [G0601943]
- Lily Foundation
- UK NHS Specialist Commissioners funds the 'Rare Mitochondrial Disorders of Adults and Children' Diagnostic Service in Newcastle upon Tyne
- Medical Research Council [G0601943, MR/K000608/1] Funding Source: researchfish
- MRC [G0601943, MR/K000608/1] Funding Source: UKRI
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-tRNAAla 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-tRNAAla variants. Previously described mt-tRNAAla 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.
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