Human Molecular Genetics Advance Access originally published online on November 21, 2008
Human Molecular Genetics 2009 18(4):714-722; 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 2 Department of Pathology, Columbia University Medical Center, 1150 St. Nicholas Avenue, Russ Berrie Medical Pavilion, Room 317, New York, NY 10032, USA 3 Department of Neurology, Hospital Sant Joan de Deu and CIBER-ER, Instituto de Salud Carlos III, Barcelona, Spain 4 Nevada Cancer Institute, Las Vegas, NV, USA 5 Department of Radiology, Weill Medical College, New York, NY, USA
* To whom correspondence should be addressed. Tel: +1 2123051048; Fax: +1 2123053986; Email: mh29{at}columbia.edu
Received October 27, 2008; Accepted November 19, 2008
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.