Human Molecular Genetics Advance Access published online on November 21, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn401
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Unbalanced deoxynucleotide pools cause mitochondrial DNA instability in thymidine phosphorylase deficient mice
1 Department of Neurology, Columbia University Medical Center, New York, NY, United States 2 Department of Neurology, Hospital Sant Joan de Deu, and CIBER-ER, Instituto de Salud Carlos III, Barcelona 3 Department of Pathology, Columbia University Medical Center, New York, NY, United States 4 Nevada Cancer Institute, Las Vegas, NV, United States 5 Department of Radiology, Weill Medical College, New York, NY, United States
* To whom correspondence should be addressed: Michio Hirano, MD, Columbia University Medical Center, 1150 St. Nicholas Ave., Russ Berrie Medical Pavilion, Room 317, New York, NY 10032, Tel: 212-305-1048, Fax: 212-305-3986, e-mail: mh29{at}columbia.edu
Received October 27, 2008; Revised November 19, 2008; Accepted November 19, 2008
Replication and repair of DNA require equilibrated pools of deoxynucleosides 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 (dTTP). 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.