Accumulation of somatic nucleotide substitutions in mitochondrial DNA associated with the 3243 A-to-G tRNA(leu)(UUR) mutation in encephalomyopathy and cardiomyopathy

Biochem Biophys Res Commun. 1996 May 15;222(2):201-7. doi: 10.1006/bbrc.1996.0722.


To understand the pathogenesis of mitochondrial encephalomyopathy and cardiomyopathy, we analyzed the sequence heterogeneity of the skeletal muscle mitochondrial DNA from a patient with Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS). A mtDNA segment of 347 bp amplified from the total DNA was cloned into a vector. Analysis of 60 independent clones (20,800 bp in total) revealed the 3243 A-->G transition in all the sequenced clones and additional nucleotide substitutions at 5 sites in 10 clones. The frequency of mutant clones (10/60) in the MELAS patient was significantly higher [chi2 = 10.909, P < 0.05] than that in an age-matched skeletal muscle control (0/60) as well as in a normal placenta (2/60). These results support our hypothesis that secondary somatic mtDNA mutations can be initiated by the 3243 A-->G mutation and that the accumulation of somatic mutation in individuals with deleterious inherited mitochondrial genotype can contribute to the progressive mitochondrial dysfunction in MELAS.

Publication types

  • Case Reports
  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Base Sequence
  • Biopsy
  • Codon
  • DNA Primers
  • DNA, Mitochondrial / chemistry*
  • DNA, Mitochondrial / metabolism
  • Female
  • Humans
  • MELAS Syndrome / genetics*
  • MELAS Syndrome / metabolism
  • Male
  • Molecular Sequence Data
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Placenta
  • Point Mutation*
  • Polymerase Chain Reaction
  • Pregnancy
  • RNA, Transfer, Leu / biosynthesis
  • RNA, Transfer, Leu / genetics*
  • Reference Values


  • Codon
  • DNA Primers
  • DNA, Mitochondrial
  • RNA, Transfer, Leu