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Human Molecular Genetics Advance Access originally published online on November 12, 2003
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Human Molecular Genetics, 2004, Vol. 13, No. 1 91-101
DOI: 10.1093/hmg/ddh010
© 2004 Oxford University Press

ND5 is a hot-spot for multiple atypical mitochondrial DNA deletions in mitochondrial neurogastrointestinal encephalomyopathy

Yutaka Nishigaki, Ramon Martí and Michio Hirano*

Department of Neurology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA

Received September 20, 2003; Revised October 28, 2003; Accepted November 3, 2003

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive multisystem disorder associated with depletion, multiple deletions and site-specific point mutations of mitochondrial DNA (mtDNA). MNGIE is caused by loss-of-function mutations in the gene encoding thymidine phosphorylase (TP; endothelial cell growth factor 1). Deficiency of TP leads to dramatically elevated levels of circulating thymidine and deoxyuridine. The alterations of pyrimidine nucleoside metabolism are hypothesized to cause imbalances of mitochondrial nucleotide pools that, in turn, may cause somatic alterations of mtDNA. We have now identified five major forms of mtDNA deletions in the skeletal muscle of MNGIE patients. While direct repeats and imperfectly homologous sequences appear to mediate the formation of mtDNA deletions, the nicotinamide adenine dinucleotide dehydrogenase 5 gene is a hot-spot for these rearrangements. A novel aspect of the mtDNA deletions in MNGIE is the presence of microdeletions at the imperfectly homologous breakpoints.

* To whom correspondence should be addressed at: Columbia University College of Physicians and Surgeons, 630 West 168th Street, P&S 4-443, New York, NY 10032, USA. Tel: +1 2123051048; Fax: +1 2123053986; Email: mh29{at}columbia.edu


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