title: The mitochondrial tRNA(Leu(UUR)) mutation in mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS): genetic, biochemical, and morphological correlations in skeletal muscle.
abstract: Mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) has recently been associated with an A----G transition at position 3243 within the mitochondrial tRNA(Leu(UUR)) gene. Besides altering the tRNA(Leu(UUR)) sequence, this point mutation lies within a DNA segment responsible for transcription termination of the rRNA genes. We have studied the distribution and expression of mutant mtDNAs in muscle biopsies from MELAS patients. Histochemical, immunohistochemical, and single-fiber PCR analysis showed that ragged-red fibers (RRF) are associated both with high levels of mutant mitochondrial genomes (greater than 85% mutant mtDNA) and with a partial cytochrome c oxidase deficiency. By quantitative in situ hybridization, the steady-state ratios of mRNAs:rRNAs were found to be similar to controls in six of eight patients studied. In two other patients the relative levels of heavy-strand mRNAs were slightly increased, but a patient with myoclonic epilepsy and RRF also exhibited a similar increase. These results directly correlate the A----G transition at mtDNA position 3243 with muscle mitochondrial proliferation, partial respiratory-chain impairment, decreased mitochondrially synthesized protein content, and no specific alterations in mitochondrial ratios of mRNAs:rRNAs.
authors.affiliation: H. Houston Merritt Clinical Research Center for Muscular Dystrophy and Related Disorders, Columbia University College of Physicians and Surgeons, New York, NY 10032.
authors.forename: C T
authors.initials: CT
authors.lastname: Moraes
authors.forename: E
authors.initials: E
authors.lastname: Ricci
authors.forename: E
authors.initials: E
authors.lastname: Bonilla
authors.forename: S
authors.initials: S
authors.lastname: DiMauro
authors.forename: E A
authors.initials: EA
authors.lastname: Schon
mesh_terms: D000140:Acidosis, Lactic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D002561:Cerebrovascular Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004272:DNA, Mitochondrial / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008931:Mitochondria, Muscle / Q000378:metabolism / Q000473:pathology; D009132:Muscles / Q000378:metabolism* / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics; D009468:Neuromuscular Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009693:Nucleic Acid Hybridization; D016133:Polymerase Chain Reaction; D012356:RNA, Transfer, Leu / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D012356:RNA, Transfer, Leu; D003576:Electron Transport Complex IV