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: Robert McFarland, Andrew M Schaefer, Julie L Gardner, Stephen Lynn, Christine M Hayes, Martin J Barron, Mark Walker, Patrick F Chinnery, Robert W Taylor, Douglass M Turnbull
• Journal: Annals of neurology (Ann Neurol) Vol. 55 Issue 4 Pg. 478-84 (Apr 2004) ISSN: 0364-5134 [Print] United States
• PMID: 15048886 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Mitochondrial
• RNA, Transfer, Glu
• RNA
• Cytosine
• Thymine

Topics

• Adolescent
• Adult
• Cells, Cultured
• Cytosine
• Female
• Fibroblasts (metabolism)
• Histocytochemistry
• Humans
• Male
• Middle Aged
• Mitochondrial Myopathies (genetics, metabolism, pathology)
• Muscle, Skeletal (metabolism, pathology)
• Mutation
• Pedigree
• Protein Biosynthesis
• RNA (genetics)
• RNA, Mitochondrial
• RNA, Transfer, Glu (genetics)
• Sequence Analysis, DNA
• Thymine