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

Abstract

A growing body of evidence has highlighted the role of abnormal DNA methylation patterns on inappropriate gene expression and promotion of disease. [1][2][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 677CRT 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. 11Recently, 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 a glutamate to alanine substitution within the C-terminal regulatory domain of the MTHFR protein. Subjects harbouring the 1298CC genotype have reduced enzyme activity but to a lesser extent than those bearing the 677TT genotype, probably because of the distinct locations of the two polymorphisms; the 677CRT and 1298ARC mutations are found in regions encoding the N-terminal catalytic and the C-terminal regulatory domains of the protein, respectively. 13 The effects of the 1298ARC mutation on plasma concentrations of tHcy remain controversial; we have recently reported that this MTHFR mutation displayed a significant effect on plasma tHcy levels, 14 but others have either not found any effect 12 15 or have found an association with even lower levels of plasma tHcy in homozygous individuals. 16 Although it was recently reported that the 677CRT transition in the MTHFR gene affects genomic DNA methylation, 3 17 the effect of the 1298ARC transversion has not bee...

MTHFR677TT genotype and disease risk: is there a modulating role for B-vitamins?

“…Given the established protective effects however, of folic acid supplementation on the occurrence and reoccurrence of NTD, polymorphisms in genes encoding the proteins that are directly involved in folate metabolism, uptake and transport have been investigated. The reduced activity of the MTHFR enzyme in individuals with the MTHFR 677TT genotype, decreases the availability of 5-methyltetrahydrofolate which plays a key role in methylation (10) and decreases global DNA methylation (63,64) ; therefore, it is no surprise that this specific mutant gene has been extensively investigated as a genetic risk factor for NTD (65,66) . Over the past two decades, several reports have shown a 2 to 4-fold increased risk of NTD if the infant or the mother has the MTHFR 677TT genotype (65,(67)(68)(69)(70) .…”

Neural tube defects and folate: case far from closed

“…4). Interestingly, the 677 TT genotype results in a global reduction in the methylation of DNA 78,79 . Moreover, reduced methylation due to the MTHFR 677 TT genotype might be more pronounced under low-to-normal folate conditions, which would be indicated by elevated homocysteine concentrations 56,57 .…”

Prospects for Epigenetic Epidemiology

“…The rate of passage through this cycle can be influenced by genetic polymorphisms that encode the enzymes involved (27). The C-to-T substitution at nucleotide 677 of the methylenetetrahydrofolate reductase gene, MTHFR (677C>T), for example, results in a more thermolabile enzyme, and TT homozygous individuals, compared with CC homozygous individuals, have lower levels of DNA methylation (28,29).…”