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A mitochondrial DNA duplication as a marker of skeletal muscle specific mutations in the mitochondrial genome
  1. M Mancuso1,
  2. C Vives-Bauza3,
  3. M Filosto1,
  4. R Marti3,
  5. A Solano2,
  6. J Montoya2,
  7. J Gamez3,
  8. S DiMauro1,
  9. A L Andreu3
  1. 1Departments of Neurology, Columbia University College of Physicians and Surgeons, New York, NY, USA
  2. 2Departamento de Bioquimica y Biologia Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain
  3. 3Centre d’Investigacions en Bioquimica i Biologia Molecular, University Hospital Vall d’Hebron, Barcelona, Spain
  1. Correspondence to:
 Dr A L Andreu
 Centre d’Investigacions en Bioquimica i, Biología Molecular, Hospital General Vall d’Hebron, P. Vall d’Hebron 119-129, 08035 Barcelona, Spain;

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Mitochondrial myopathies are often associated with point mutations in mitochondrial DNA (mtDNA), and are usually maternally inherited. However, they may also present as an isolated myopathy, often with ptosis and ophthalmoparesis,1 or with isolated exercise intolerance.2 In eight patients with exercise intolerance described by us in 1999,2 there was no evidence of maternal inheritance, muscle histochemistry showed cytochrome c oxidase (COX) positive ragged red fibres, biochemistry showed complex III deficiency, and molecular genetic analysis revealed different mutations in the mitochondrial cytochrome b gene (CYB). Several other patients with lifelong exercise intolerance harboured mutations in other mtDNA protein coding genes.3 Characteristically, these mutations are not maternally inherited and are abundant (more than 90%) in skeletal muscle, where they coexist with smaller amounts of wild type mtDNA genomes. As a rule, the mutations are not present in other tissues and, surprisingly, are not found in cultured myoblasts, indicating that they are somatic mutations of skeletal muscle. However, the mechanism by which these mutations accumulate in muscle remains unknown.

As the clinical presentation of all patients (lifelong progression of clinical symptoms), suggested that the molecular defect may accumulate over time, we looked for duplications in the D-loop as putative sources of replication advantage or disadvantage for mutant mtDNAs. Here, we report our findings in 10 patients harbouring different mtDNA mutations restricted to skeletal muscle; 5 patients with point mutations and 5 with single deletions. In all five patients with point mutations, we identified a 652 bp duplication in the mtDNA control region, which altered the promoter and replication elements. The duplication was restricted to skeletal muscle mtDNA, and analysis of subcloned PCR fragments encompassing both the site of the point mutation and the region of the duplication suggested that the duplication segregates independently from the point mutation. Our …

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  • The first two authors contributed equally to this work