title: Unbalanced deoxynucleotide pools cause mitochondrial DNA instability in thymidine phosphorylase-deficient mice.
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.
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Luis C
authors.initials: LC
authors.lastname: López
authors.forename: Hasan O
authors.initials: HO
authors.lastname: Akman
authors.forename: Angeles
authors.initials: A
authors.lastname: García-Cazorla
authors.forename: Beatriz
authors.initials: B
authors.lastname: Dorado
authors.forename: Ramón
authors.initials: R
authors.lastname: Martí
authors.forename: Ichizo
authors.initials: I
authors.lastname: Nishino
authors.forename: Saba
authors.initials: S
authors.lastname: Tadesse
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pizzorno
authors.forename: Dikoma
authors.initials: D
authors.lastname: Shungu
authors.forename: Eduardo
authors.initials: E
authors.lastname: Bonilla
authors.forename: Kurenai
authors.initials: K
authors.lastname: Tanji
authors.forename: Michio
authors.initials: M
authors.lastname: Hirano
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D003854:Deoxyribonucleotides / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D042822:Genomic Instability; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011686:Purine-Pyrimidine Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism*; D013939:Thymidine Phosphorylase / Q000172:deficiency* / Q000235:genetics; D014543:Uridine Phosphorylase / Q000235:genetics / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial; D003854:Deoxyribonucleotides; D014543:Uridine Phosphorylase; D013939:Thymidine Phosphorylase; D042967:Electron Transport Complex I