Title | Unbalanced deoxynucleotide pools cause mitochondrial DNA instability in thymidine phosphorylase-deficient mice. |
Publication Type | Journal Article |
Year of Publication | 2009 |
Authors | López LC, Akman HO, García-Cazorla A, Dorado B, Martí R, Nishino I, Tadesse S, Pizzorno G, Shungu D, Bonilla E, Tanji K, Hirano M |
Journal | Hum Mol Genet |
Volume | 18 |
Issue | 4 |
Pagination | 714-22 |
Date Published | 2009 Feb 15 |
ISSN | 1460-2083 |
Keywords | Animals, Brain, Deoxyribonucleotides, DNA, Mitochondrial, Electron Transport Complex I, Genomic Instability, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular Sequence Data, Purine-Pyrimidine Metabolism, Inborn Errors, Thymidine Phosphorylase, Uridine Phosphorylase |
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. |
DOI | 10.1093/hmg/ddn401 |
Alternate Journal | Hum Mol Genet |
PubMed ID | 19028666 |
PubMed Central ID | PMC2638828 |
Grant List | R01 HD056103 / HD / NICHD NIH HHS / United States P01 NS011766-300039 / NS / NINDS NIH HHS / United States P01 NS011766-310039 / NS / NINDS NIH HHS / United States P01 NS011766-290039 / NS / NINDS NIH HHS / United States P01NS11766 / NS / NINDS NIH HHS / United States P01 NS011766 / NS / NINDS NIH HHS / United States |
Related Institute:
MRI Research Institute (MRIRI)