IMPAIRED MITOCHONDRIAL TRANSLATION IN HUMAN MYOBLASTS HARBORING THE MITOCHONDRIAL-DNA TRANSFER-RNA LYSINE-8344 A-]G (MERRF) MUTATION - RELATIONSHIP TO PROPORTION OF MUTANT MITOCHONDRIAL-DNA

The mitochondrial DNA transfer RNA lysine A8344G mutation is commonly associated with the MERRF (myoclonus epilepsy with ragged red fibre) p henotype. The molecular pathogenesis of disease associated with this m utation is unclear. Theoretically, a mitochondrial tRNA mutation might affect transcription or translation, or both. We therefore studied th ese processes in cloned primary human myoblast cultures containing dif ferent proportions of mutant mtDNA. No abnormality of transcription wa s observed. However, there was a progressive decrease in mitochondrial ly encoded protein synthesis as the proportion of mutant mtDNA increas ed. Furthermore, there was evidence that subunits were differentially affected, based on selective reduction of cytochrome c oxidase subunit s with relatively low proportions of mutant mtDNA.