Molecular Biology of Methylenetetrahydrofolate Reductase (MTHFR): Interrelationships with Folic Acid, Homocysteine and Vascular Disease

Summary

Methylenetetrahydrofolate reductase (MTHFR) is required for the synthesis of 5-methyltetrahydrofolate, a methyl donor for homocysteine remethylation to methionine. Severe deficiency of MTHFR is associated with the inborn error of metabolism, homocystinuria, whereas a milder deficiency of the enzyme is associated with mild to moderate hyperhomocysteinemia. The isolation of the cDNA and gene for human MTHFR has made it possible to study MTHFR deficiency at the molecular level. Eighteen rare MTHFR mutations have been identified in patients with homocystinuria. Five common variants in MTHFR have been reported, but only one, 677 C→T (an alanine to valine substitution), has been consistently demonstrated to influence homocysteine levels. Individuals with the homozygous mutant genotype can overcome the effect of the mutation by maintaining adequate folate levels. The frequency of the homozygous mutant genotype ranges from 11% – 15% of North Americans and 5% – 23% of Europeans. Several, but not all, studies have reported an increased risk of vascular disease for individuals with the homozygous mutant genotype. The influence of the genotype on disease risk is dependent on nutritional status (folate level), as well as on the number of other more traditional risk factors present in the study group, supporting the multifactorial nature of cardiovascular disease.