The mitochondrial tRNA(Leu)(UUR)) mutation in MELAS: a model for pathogenesis.
The A----G transition at nucleotide 3243 of the mitochondrial tRNA(Leu)(UUR)) gene has been associated with MELAS, a maternally-inherited mitochondrial disorder. We recently transferred mitochondria harboring this mtDNA mutation into a human cell line devoid of endogenous mtDNA (rho degrees cells), and showed: (1) decreased rate of synthesis and of steady-state levels of mitochondrial translational products, (2) reduced respiratory chain function and (3) increased amounts of a novel unprocessed RNA species (termed by us RNA 19) derived from transcription of the 16S rRNA + tRNA(Leu)(UUR) + ND 1 genes. Because RNA 19 contains rRNA sequences, we propose that this molecule is incorporated into mitochondrial ribosomes, and interferes disproportionately with mitochondrial translation, thereby causing the phenotypic changes associated with MELAS.
Schon
E A
EA
Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
Koga
Y
Y
Davidson
M
M
Moraes
C T
CT
King
M P
MP
D001928:Brain Diseases, Metabolic / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000235:genetics; D006801:Humans; D008052:Lipid Metabolism, Inborn Errors / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D008957:Models, Genetic; D009135:Muscular Diseases / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D012313:RNA / Q000235:genetics*; D000077278:RNA, Mitochondrial; D012356:RNA, Transfer, Leu / Q000235:genetics*
D004272:DNA, Mitochondrial; D000077278:RNA, Mitochondrial; D012356:RNA, Transfer, Leu; D012313:RNA