Pathogenic mitochondrial mt-tRNA Ala variants are uniquely associated with isolated myopathy

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Abstract

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.

Figures

  • Figure 1 Identification of novel mt-tRNAAla variants (a) Sequencing electropherogram (reverse sequence) demonstrating the heteroplasmic m.5631G4A transition detected in patient muscle. (b) Sequencing electropherogram demonstrating the heteroplasmic m.5610G4A transition detected in muscle. (c) Schematic representation of the mt-RNAAla cloverleaf structure, illustrating the position of the novel m.5631G4A and m.5610G4A variants and other reported mt-tRNAAla mutations. Phylogenetic conservation of the appropriate regions of the mt-tRNAAla gene sequence for both (d) m.5631G4A and (e) m.5610G4A indicates that both variants affect an evolutionary conserved residue.
  • Figure 2 Molecular genetic investigations of patients’ muscle with the novel m.5631G4A and m.5610G4A variants (a) Patient 1’s pedigree including mtDNA mutation heteroplasmy levels in the index case and her mother. (b) Family pedigree including mtDNA mutation heteroplasmy levels in the index case (Patient 2) and other family members. (c) Single-fibre PCR analysis of the m.5631G4A mutation segregates with a biochemical defect in individual COXdeficient muscle fibres. (d) Single-fibre PCR analysis of the m.5610G4A mutation segregates with a biochemical defect in individual COX-deficient muscle fibres. (e) Measurement of mt-tRNAAla steady-state levels in muscle showing dramatically decreased mt-tRNAAla steady-state levels in both patients.
  • Table 1 Clinical, histochemical and molecular details of the novel mt-tRNAAla mutations and previously reported mt-tRNAAla mutations

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Lehmann, D., Schubert, K., Joshi, P. R., Hardy, S. A., Tuppen, H. A. L., Baty, K., … Taylor, R. W. (2015). Pathogenic mitochondrial mt-tRNA Ala variants are uniquely associated with isolated myopathy. European Journal of Human Genetics, 23(12), 1735–1738. https://doi.org/10.1038/ejhg.2015.73

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