Molecular biology of 5,10-methylenetetrahydrofolate reductase

Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the folate cycle and contributes to the metabolism of the amino acid homocysteine. It catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, thus generating the active form of folate required for remethylation of homocysteine to methionine. Deficiency of MTHFR may be associated with an increase in plasma homocysteine, which in turn is associated with an increased risk of vascular disease. This article summarizes the biochemistry, the function in the folate cycle, and the molecular genetics of this enzyme. Particular emphasis has been given to the role of two common polymorphisms (MTHFR 677C-->T, 1298A-->C) in cardiovascular disease, cerebrovascular disease, venous thrombosis, longevity, neural tube defects, pregnancy/preeclampsia, diabetes, cancer, psychiatry, renal failure and renal replacement therapy. Finally, the rare genetic defects underlying severe MTHFR deficiency are also considered.