Variable distribution of mutant mitochondrial DNAs (tRNA(Leu[3243])) in tissues of symptomatic relatives with MELAS: the role of mitotic segregation

Neurology. 1993 Aug;43(8):1586-90. doi: 10.1212/wnl.43.8.1586.


We studied multiple different postmortem tissue samples from a woman and two of her daughters with the MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) tRNA(Leu(UUR)) mutation at nucleotide 3243 in mitochondrial DNA (mtDNA). All tissues examined were heteroplasmic for the mutation. The mean proportion of mutant mtDNAs in the mother's tissues (0.30 +/- 0.10) was significantly lower than that of each of her daughters' (0.76 +/- 0.11, p < 0.03, and 0.72 +/- 0.13, p < 0.001); there was no difference in the fraction of mutant mtDNAs between the daughters (p < 0.71). This difference in the mean proportion of mtDNA mutants between family members correlates with their clinical profiles; the mother had the latest onset of disease and lived longest, while the two daughters had a strikingly similar clinical course. In individual patients, the mean proportion of mutant mtDNAs was not different in tissues deriving from ectodermal, mesodermal, and endodermal germ layers. Variance in the mutant:wild-type mtDNA ratio was normally distributed about the mean, both when all tissues were considered together and when different regions of the CNS were considered separately. Thus, the proportion of mtDNAs carrying the tRNA(Leu(3243)) mutation was not uniform in members of this pedigree and did not undergo rapid mitotic segregation along germ-layer divisions. These findings are consistent with the hypothesis that the overall proportion of mtDNAs carrying this mutation is primarily determined by segregation during oogenesis or early embryologic development and that random replicative (mitotic) segregation, subsequent to the establishment of primary germ layers, is responsible for the variation between tissues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • DNA, Mitochondrial / genetics*
  • Female
  • Humans
  • MELAS Syndrome / genetics*
  • MELAS Syndrome / pathology
  • Mitosis
  • Mutation
  • Pedigree
  • RNA, Transfer, Leu / analysis*


  • DNA, Mitochondrial
  • RNA, Transfer, Leu