Unbalanced deoxynucleotide pools cause mitochondrial DNA instability in thymidine phosphorylase-deficient mice

Hum Mol Genet. 2009 Feb 15;18(4):714-22. doi: 10.1093/hmg/ddn401. Epub 2008 Nov 21.

Abstract

Replication and repair of DNA require equilibrated pools of deoxynucleoside triphosphate precursors. This concept has been proven by in vitro studies over many years, but in vivo models are required to demonstrate its relevance to multicellular organisms and to human diseases. Accordingly, we have generated thymidine phosphorylase (TP) and uridine phosphorylase (UP) double knockout (TP(-/-)UP(-/-)) mice, which show severe TP deficiency, increased thymidine and deoxyuridine in tissues and elevated mitochondrial deoxythymidine triphosphate. As consequences of the nucleotide pool imbalances, brains of mutant mice developed partial depletion of mtDNA, deficiencies of respiratory chain complexes and encephalopathy. These findings largely account for the pathogenesis of mitochondrial neurogastrointestinal encephalopathy (MNGIE), the first inherited human disorder of nucleoside metabolism associated with somatic DNA instability.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • DNA, Mitochondrial / chemistry*
  • DNA, Mitochondrial / genetics
  • DNA, Mitochondrial / metabolism
  • Deoxyribonucleotides / metabolism*
  • Electron Transport Complex I / genetics
  • Electron Transport Complex I / metabolism
  • Genomic Instability*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • Purine-Pyrimidine Metabolism, Inborn Errors / genetics
  • Purine-Pyrimidine Metabolism, Inborn Errors / metabolism*
  • Thymidine Phosphorylase / deficiency*
  • Thymidine Phosphorylase / genetics
  • Uridine Phosphorylase / genetics
  • Uridine Phosphorylase / metabolism*

Substances

  • DNA, Mitochondrial
  • Deoxyribonucleotides
  • Uridine Phosphorylase
  • Thymidine Phosphorylase
  • Electron Transport Complex I

Associated data

  • GENBANK/AB042432
  • GENBANK/AB042524
  • GENBANK/AB042809
  • GENBANK/AB049457
  • GENBANK/AJ489607
  • GENBANK/AJ512208
  • GENBANK/AY339599
  • GENBANK/AY533105
  • GENBANK/AY533106
  • GENBANK/AY533107
  • GENBANK/AY533108
  • GENBANK/DQ106412
  • GENBANK/EF108330
  • GENBANK/EF108331
  • GENBANK/EF108333
  • GENBANK/EF108334
  • GENBANK/EF108335
  • GENBANK/EF108337
  • GENBANK/EF108338
  • GENBANK/EF108339
  • GENBANK/EF108341
  • GENBANK/EF108342
  • GENBANK/EF108343
  • GENBANK/EF108344
  • GENBANK/EF108345
  • GENBANK/J01442
  • GENBANK/L07095
  • GENBANK/L07096
  • RefSeq/NC_005089