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. Ann Neurol 2004;55:000–000