Contrasting phenotypes in three patients with novel mutations in mitochondrial tRNA genes

Roberto Anitori, Kara Manning, Franklin Quan, Richard G. Weleber, Neil R.M. Buist, Eric A. Shoubridge, Nancy G. Kennaway

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


We studied three patients, each harboring a novel mutation at a highly conserved position in a different mitochondrial tRNA gene. The mutation in patient 1 (T5543C) was associated with isolated mitochondrial myopathy, and occurred in the anticodon loop of tRNATrp. In patient 2, with mitochondrial myopathy and marked retinopathy, the mutation (G14710A) resulted in an anticodon swap (Glu to Lys) in tRNAGlu. Patient 3, who manifested mitochondrial encephalomyopathy and moderate retinal dysfunction, harbored a mutation (C3287A) in the TψC loop of tRNALeu(UUR). The mutations were heteroplasmic in muscle in all cases, and sporadic in two cases. PCR-RFLP analysis in all patients showed much higher amounts of mutated mtDNA in affected tissue (muscle) than unaffected tissue (blood), and significantly higher levels of mutated mtDNA in cytochrome c oxidase (COX)-negative muscle fibers than in COX-positive fibers, confirming the pathogenicity of these mutations. The mutation was also detected in single hair roots from all three patients, indicating that each mutation must have arisen early in embryonic development or in maternal germ cells. This suggests that individual hair root analyses may reflect a wider tissue distribution of mutated mtDNA than is clinically apparent, and might be useful in predicting prognosis and, perhaps, the risk of transmitting the mutation to offspring. Our data suggest a correlation between clinical phenotype and distribution of mutated mtDNA in muscle versus hair roots. Furthermore, the high threshold for phenotypic expression in single muscle fibers (92-96%) suggests that therapies may only need to increase the percentage of wild-type mtDNA by a small amount to be beneficial.

Original languageEnglish (US)
Pages (from-to)176-188
Number of pages13
JournalMolecular Genetics and Metabolism
Issue number2
StatePublished - Feb 2005
Externally publishedYes


  • Complex I deficiency
  • Complex IV deficiency
  • Cytochrome c oxidase negative fibers
  • Hair root analysis
  • Mitochondrial DNA
  • Mitochondrial encephalomyopathy
  • Mitochondrial myopathy
  • Mitochondrial tRNA mutation
  • Pigmentary retinopathy

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology


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