title: Familial myopathy: new insights into the T14709C mitochondrial tRNA mutation.
abstract: We have defined the genetic defect in a large family first described in one of the earliest reports of suspected mitochondrial myopathy, as the mutation T14709C in the mitochondrial transfer RNA(Glu) (mt-tRNA(Glu)) gene. Extraordinarily, this mutation has attained homoplasmy (100% mutated mt-tRNA(Glu)) on at least three independent occasions in this family and has done so in one individual who remains asymptomatic with no clinical evidence of disease. Heteroplasmy (dual populations of mutated and wild-type mtDNA) usually is regarded as one of the primary diagnostic criteria for pathogenicity and previous reports of the T14709C mutation detail heteroplasmy in a variety of tissues. In contrast, homoplasmy of mt-tRNA mutations generally has been regarded as evidence of a benign nature, with rare exceptions that result in organ-specific phenotypes. Discovering that T14709C, a common and severe mt-tRNA mutation, can attain homoplasmy without symptoms or clinical signs of disease has profound implications for the identification and prevalence of other pathogenic mt-tRNA mutations. Furthermore, variation in phenotype between homoplasmic individuals implies a crucial contribution from the nuclear genetic environment in determining the clinical outcome of mt-tRNA mutations.
authors.affiliation: Mitochondrial Research Group, School of Neurology, Neurobiology and Psychiatry, The Medical School, University of Newcastle upon Tyne, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: McFarland
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Schaefer
authors.forename: Julie L
authors.initials: JL
authors.lastname: Gardner
authors.forename: Stephen
authors.initials: S
authors.lastname: Lynn
authors.forename: Christine M
authors.initials: CM
authors.lastname: Hayes
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Barron
authors.forename: Mark
authors.initials: M
authors.lastname: Walker
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.forename: Douglass M
authors.initials: DM
authors.lastname: Turnbull
mesh_terms: D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D003596:Cytosine; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006651:Histocytochemistry; D006801:Humans; D008297:Male; D008875:Middle Aged; D017240:Mitochondrial Myopathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D010375:Pedigree; D014176:Protein Biosynthesis; D012313:RNA / Q000235:genetics*; D000077278:RNA, Mitochondrial; D012352:RNA, Transfer, Glu / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013941:Thymine
chemical_list: D000077278:RNA, Mitochondrial; D012352:RNA, Transfer, Glu; D012313:RNA; D003596:Cytosine; D013941:Thymine