Thymidine phosphorylase mutations cause instability of mitochondrial DNA.
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder characterized by ptosis and progressive external ophthalmoplegia, peripheral neuropathy, severe gastrointestinal dysmotility, cachexia and leukoencephalopathy. Muscle biopsies of MNGIE patients have revealed morphologically abnormal mitochondria and defects of respiratory chain enzymes. In addition, patients harbor depletion, multiple deletions, and point mutations of mitochondrial DNA (mtDNA). This disorder is caused by loss-of-function mutations in the gene encoding thymidine phosphorylase (TP) a cytosolic enzyme. In MNGIE patients, TP activity is very low or absent resulting in dramatically elevated levels of plasma thymidine and deoxyuridine. We have hypothesized that the increased levels of thymidine and deoxyuridine cause mitochondrial nucleotide pool imbalances that, in turn, generate mtDNA alterations.
Hirano
Michio
M
Department of Neurology, Columbia University College of Physicians and Surgeons, 630 West 168th Street, P&S 4-443, New York, NY 10032, USA. mh29@columbia.edu
Lagier-Tourenne
Clotilde
C
Valentino
Maria L
ML
Martí
Ramon
R
Nishigaki
Yutaka
Y
D004272:DNA, Mitochondrial / Q000235:genetics*; D003857:Deoxyuridine / Q000097:blood; D006801:Humans; D007668:Kidney / Q000378:metabolism; D017237:Mitochondrial Encephalomyopathies / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008954:Models, Biological; D009154:Mutation; D013936:Thymidine / Q000097:blood / Q000378:metabolism; D013939:Thymidine Phosphorylase / Q000235:genetics* / Q000378:metabolism
D004272:DNA, Mitochondrial; D013939:Thymidine Phosphorylase; D013936:Thymidine; D003857:Deoxyuridine