Site-specific somatic mitochondrial DNA point mutations in patients with thymidine phosphorylase deficiency

J Clin Invest. 2003 Jun;111(12):1913-21. doi: 10.1172/JCI17828.


Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by loss-of-function mutations in the gene encoding thymidine phosphorylase (TP). This deficiency of TP leads to increased circulating levels of thymidine (deoxythymidine, dThd) and deoxyuridine (dUrd) and has been associated with multiple deletions and depletion of mitochondrial DNA (mtDNA). Here we describe 36 point mutations in mtDNA of tissues and cultured cells from MNGIE patients. Thirty-one mtDNA point mutations (86%) were T-to-C transitions, and of these, 25 were preceded by 5'-AA sequences. In addition, we identified a single base-pair mtDNA deletion and a TT-to-AA mutation. Next-nucleotide effects and dislocation mutagenesis may contribute to the formation of these mutations. These results provide the first demonstration that alterations of nucleoside metabolism can induce multiple sequence-specific point mutations in humans. We hypothesize that, in patients with TP deficiency, increased levels of dThd and dUrd cause mitochondrial nucleotide pool imbalances, which, in turn, lead to mtDNA abnormalities including site-specific point mutations.

Publication types

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

MeSH terms

  • Base Sequence
  • Cells, Cultured
  • DNA Mutational Analysis
  • DNA, Mitochondrial / genetics*
  • Deoxyuridine / metabolism
  • Electron Transport Complex IV / metabolism
  • Gastrointestinal Diseases / enzymology
  • Gastrointestinal Diseases / genetics
  • Humans
  • Mitochondrial Encephalomyopathies / enzymology*
  • Mitochondrial Encephalomyopathies / genetics*
  • Models, Genetic
  • Point Mutation*
  • Polymorphism, Restriction Fragment Length
  • Sequence Deletion
  • Thymidine Phosphorylase / deficiency*
  • Thymidine Phosphorylase / genetics*


  • DNA, Mitochondrial
  • Electron Transport Complex IV
  • Thymidine Phosphorylase
  • Deoxyuridine