The mitochondrial tRNA(Leu(UUR)) mutation in mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS): genetic, biochemical, and morphological correlations in skeletal muscle

Am J Hum Genet. 1992 May;50(5):934-49.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acidosis, Lactic / genetics*
  • Acidosis, Lactic / metabolism
  • Acidosis, Lactic / pathology
  • Adult
  • Cerebrovascular Disorders / genetics*
  • Cerebrovascular Disorders / metabolism
  • Cerebrovascular Disorders / pathology
  • DNA, Mitochondrial / genetics*
  • Electron Transport Complex IV / metabolism
  • Female
  • Gene Expression / genetics
  • Humans
  • Immunohistochemistry
  • Male
  • Mitochondria, Muscle / metabolism
  • Mitochondria, Muscle / pathology
  • Muscles / metabolism*
  • Muscles / ultrastructure
  • Mutation / genetics
  • Neuromuscular Diseases / genetics*
  • Neuromuscular Diseases / metabolism
  • Neuromuscular Diseases / pathology
  • Nucleic Acid Hybridization
  • Polymerase Chain Reaction
  • RNA, Transfer, Leu / genetics*


  • DNA, Mitochondrial
  • RNA, Transfer, Leu
  • Electron Transport Complex IV