Journal
NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS
Volume 23, Issue 8-9, Pages 1217-1225Publisher
TAYLOR & FRANCIS INC
DOI: 10.1081/NCN-200027485
Keywords
mitochondria; mitochondrial DNA; MNGIE; thymidine phosphorylase; thymidine and deoxyuridine
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Funding
- NICHD NIH HHS [R01HD37529] Funding Source: Medline
- NINDS NIH HHS [P01NS11766] Funding Source: Medline
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Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in the gene encoding thymidine phosphorylase (TP). The disease is characterized clinically by impaired eye movements, gastrointestinal dysmotility, cachexia, peripheral neuropathy, myopathy, and leukoencephalopathy. Molecular genetic studies of MNGIE patients' tissues have revealed multiple deletions, depletion, and site-specific point mutations of mitochondrial DNA. TP is a cytosolic enzyme required for nucleoside homeostasis. In MNGIE, TP activity is severely reduced and consequently levels of thymidine and deoxyuridine in plasma are dramatically elevated. We have hypothesized that the increased levels of intracellular thymidine and deoxyuridine cause imbalances of mitochondrial nucleotide pools that, in turn, lead to the mtDNA abnormalities. MNGIE was the first molecularly characterized genetic disorder caused by abnormal mitochondrial nucleoside/nucleotide metabolism. Future studies are likely to reveal further insight into this expanding group of diseases.
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