5,10-methylenetetrahydrofolate reductase (MTHFR) 677C->T and 1298A->C mutations are associated with DNA hypomethylation

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Abstract
A growing body of evidence has highlighted the role of abnormal DNA methylation patterns on inappropriate gene expression and promotion of disease.1–3 DNA methylation patterns are maintained by DNA methyltransferases,4–7 using S-adenosylmethionine (AdoMet) as the methyl group donor; AdoMet is then converted to S-adenosylhomocysteine (AdoHcy). Intracellular homocysteine (Hcy) is derived from AdoHcy hydrolysis through the action of AdoHcy hydrolase, a reversible reaction with a dynamic equilibrium that strongly favours AdoHcy synthesis rather than hydrolysis.8 Thus, an efficient metabolic removal of Hcy is required to prevent AdoHcy accumulation. The toxicity of intracellular AdoHcy accumulation lies in its high affinity binding to the catalytic region of most AdoMet dependent methyltransferases (including DNA methyltransferases), acting as its inhibitor.9 Thereby, any disturbance in Hcy metabolism is likely to disturb cellular methylation processes, including DNA methylation patterns. 5,10-methylenetetrahydrofolate reductase (MTHFR) is one of the main regulatory enzymes of Hcy metabolism that catalyses the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the methyl donor for the remethylation of Hcy to methionine. A common 677C→T transition in the MTHFR gene is a well established genetic determinant of hyperhomocysteinaemia, and results in a thermolabile protein, with a decreased enzymatic activity. The molecular basis of this thermolability is a missense mutation in the exon 4 of the MTHFR gene, a cytosine to thymine substitution at nucleotide 677, which converts an alanine to a valine codon in the N-terminal catalytic domain of the protein. The association between this MTHFR genotype and the total Hcy (tHcy) circulating levels is well known to be contingent on folate status.10,11 Recently, a second polymorphism associated with decreased enzymatic activity but not with thermolability was discovered in the MTHFR gene.12 This genetic variant corresponds to an adenosine to cytosine transversion at nucleotide 1298, in exon 7, leading to …