title: A new mtDNA mutation showing accumulation with time and restriction to skeletal muscle.
abstract: We have identified a new mutation in mtDNA, involving tRNALeu(CUN) in a patient manifesting an isolated skeletal myopathy. This heteroplasmic A-->G transition at position 12320 affects the T psi C loop at a conserved site and was not found in 120 controls. Analysis of cultured fibroblasts, white blood cells/platelets, and skeletal muscle showed that only skeletal muscle contained the mutation and that only this tissue demonstrated a biochemical defect of respiratory-chain activity. In a series of four muscle-biopsy specimens taken over a 12-year period, there was a gradual increase, from 70% to 90%, in the overall level of mutation, as well as a marked clinical deterioration. Single-fiber PCR confirmed that the proportion of mutant mtDNA was highest in cytochrome c oxidase-negative fibers. This study, which reports a mutation involving tRNALeu(CUN), demonstrates clearly that mtDNA point mutations can accumulate over time and may be restricted in their tissue distribution. Furthermore, clinical deterioration seemed to follow the increase in the level of mutation, although, interestingly, the appearance of fibers deficient in respiratory-chain activity showed a lag period.
authors.affiliation: Division of Neurology, The Medical School, Newcastle upon Tyne, United Kingdom.
authors.forename: K
authors.initials: K
authors.lastname: Weber
authors.forename: J N
authors.initials: JN
authors.lastname: Wilson
authors.forename: L
authors.initials: L
authors.lastname: Taylor
authors.forename: E
authors.initials: E
authors.lastname: Brierley
authors.forename: M A
authors.initials: MA
authors.lastname: Johnson
authors.forename: D M
authors.initials: DM
authors.lastname: Turnbull
authors.forename: L A
authors.initials: LA
authors.lastname: Bindoff
mesh_terms: D001483:Base Sequence; D002478:Cells, Cultured; D003580:Cytochromes / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000378:metabolism; D017240:Mitochondrial Myopathies / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009690:Nucleic Acid Conformation; D017354:Point Mutation; D012346:RNA, Transfer, Amino Acyl / Q000737:chemistry / Q000235:genetics*; D013386:Succinates / Q000378:metabolism; D019802:Succinic Acid
chemical_list: D003580:Cytochromes; D004272:DNA, Mitochondrial; D012346:RNA, Transfer, Amino Acyl; D013386:Succinates; D018698:Glutamic Acid; D019802:Succinic Acid; D003576:Electron Transport Complex IV