Phenotypical expression and molecular genetics of the nt-3243 mutation in the mitochondrial tRNA(LEU(UUR)) gene

The morphological and genetic characteristics of isolated muscle fibers from patients harboring an A->G mutation at nt-3243 in the mitochondrial tRNA(Leu(UUR)) gene have been analysed. This mutation is associated with two distinct disorders, namely, mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS³²⁴³) and progressive external ophthalmoplegia (PEO³²⁴³). Morphologically, the main distinctive feature in PEO³²⁴³ muscle sections is the presence of a subset of ragged-red fibers (RRF) with no cytochrome c oxidase activity, a feature which is present only rarely in MELAS³²⁴³ muscle. By single fiber PCR analysis, we have found that the two disorders exhibit a distinctive pattern in muscle of the distribution of the nt-3243 mutation. Furthermore, we have provided evidence that the focal concentration of the nt-3243 mutation in single muscle fibers induces impairment of respiratory chain function.