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Methylentetrahydrofolatreductase (MTHFR) C677TMethylentetrahydrofolatreductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate, the methyl donor for methionine synthesis and the precursor of S-adenosylmethionine. S-adenosylmethionine is the universal methyl donor for methylation reactions. Thus, MTHFR is a central enzyme in the remethylation of homocysteine to methionine. Its common thermolabile variant C677T possesses decreased activity. Clinically, homozygous mutations are associated with high homocysteine levels in patients with compromised or insufficient function of the kidneys - the major disposal organ for homocysteine. DNA methylation is an epigenetic feature of DNA that influences cellular development and function, and aberrations of DNA methylation are a candidate mechanism for the development of cancer. Since S-adenosylmethionine is the methyl donor also for DNA methylation reactions, several developmental disorders like neural tube defects (spina bifida, nonsyndromic cleft lip and Down's syndrome) but also the development of cancers and leukaemia have been linked to this mutation. Also predisposition to schizophrenia, particularly the response to neuroleptics appears related to the MTHFR genotype.References 1. Fodinger M et al. Molecular biology of 5,10-methylenetetrahydrofolate reductase. J Nephrol 2000 Jan-Feb;13(1):20-33 2. Tremblay R et al. Hyperhomocysteinemia in hemodialysis patients: effects of 12-month supplementation with hydrosoluble vitamins. Kidney Int 2000 Aug;58(2):851-8 3. Stern LL et al. Genomic DNA hypomethylation, a characteristic of most cancers, is present in peripheral leukocytes of individuals who are homozygous for the C677T polymorphism in the methylenetetrahydrofolate reductase gene. Cancer Epidemiol Biomarkers Prev 2000 Aug;9(8):849-53 4. Skibola CF et al. Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc Natl Acad Sci U S A 1999 Oct 26;96(22):12810-5 5. Hobbs CA et al. Polymorphisms in Genes Involved in Folate Metabolism as Maternal Risk Factors for Down Syndrome. Am J Hum Genet 2000 Sep;67(3):623-630 6. Piyathilake CJ et al. Methylenetetrahydrofolate reductase (MTHFR) polymorphism increases the risk of cervical intraepithelial neoplasia. Anticancer Res 2000 May-Jun;20(3A):1751-7 7. Joober R et al. Association between the methylenetetrahydrofolate reductase 677C-->T missense mutation and schizophrenia. Mol Psychiatry 2000 May;5(3):323-326 |