Thymidine Phosphorylase Gene Mutations Cause Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE)
Internal medicine (Tokyo. 1992)
woman with mitochondrial neurogastrointestinal encephalomyopathy (MNG-IE). MNGIE is an autosomal recessive disease caused by lossof-function mutations in the ECGF1 gene encoding thymidine phosphorylase (TP) (3, 4) . In MNGIE, the severe loss of TP activity (<10% of mean control TP activity) leads to markedly elevated plasma levels of thymidine and deoxyuridine nucleosides and also mtDNA alterations (4). We have identified 85 MNGIE patients with this unique combination of genetic and biochemical
... tic and biochemical alterations indicating that the ECGF1 mutations are indeed pathogenic (Hirano, unpublished observation). We have hypothesized that high concentrations of pyrimidine nucleosides cause nucleotide pool imbalance, which leads to impaired mtDNA replication, repair, or both (4). In their MNGIE patient, Dr. Kumagai and colleagues (1) identified a homozygous TP mutation, S471L and partially reduced TP enzyme activity in the peripheral blood monocytes; however, the S471L change was also homozygous in the unaffected mother. Furthermore, this TP polymorphism was present in a significant number of unrelated Japanese individuals. Based on these findings, the authors appropriately questioned the pathogenicity of this TP variant and speculated that the TP polymorphism may interact with mtDNA deletions to cause the disease. We initially reported the S471L change as pathogenic, but subsequently identified this sequence variant in controls (6 of 55 individuals of diverse ethnic backgrounds) indicating that it is not pathogenic. In conclusion, we would like to make the following points regarding this case report (1). 1) We agree that the S471L is a neutral polymorphism. 2) The genetic cause of their patient's disease has not been determined. There may be a mutation in unsequenced regions (such as promoter or introns) of the TP gene. Measurement of plasma thymidine and deoxyuridine is necessary to confirm that the patient has significant TP deficiency. Alternatively, their case is MNGIE-like but not MNGIE due to TP deficiency. 3) The authors cite the lack of mitochondrial pathology in double knock-out mice lacking TP and uridine phosphorylase activities; however, plasma of wild-type mice have significantly higher levels of thymidine and deoxyuridine (both~0.2 μM) than humans (normal <0.05 μM) (4, 5) indicating that mice are more tolerant of high concentrations of pyrimidine nucleosides than people. 4) Overall, the title of the report "Thymidine phosphorylase gene mutation is not a primary cause of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)" is not scientifically supported by their data. References 1. Kumagai Y, Sugiura Y, Sugeno H, Takebayashi Y, Takenoshita S, Yamamoto T. Thymidine phosphorylase gene mutation is not a primary cause of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Intern Med 45: 443-446, 2006. 2. Kurihara T. Mitochondrial neurogastrointestinal encephalomyopathy and its pathophysiology. Intern Med 45: 415-416, 2006. 3. Nishino I, Spinazzola A, Hirano M. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Sci-ence 283: 689-692, 1999. 4. Hirano M, Nishigaki Y, Marti R. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): A disease of two genomes. Neurologist 10: 8-17, 2004. 5. Haraguchi M, Tsujimoto H, Fukushima M, et al. Targeted deletion of both thymidine phosphorylase and uridine phosphorylase and consequent disorders in mice.