MTHFR genetics

MTHFR (methylenetetrahydrofolate reductase) is the key enzyme of methylation: in the final step it forms the active form 5-methyltetrahydrofolate (5-MTHF) from 5,10-methylenetetrahydrofolate, which is needed for homocysteine remethylation, SAMe synthesis and neurotransmitter production. The common variants C677T and A1298C reduce enzyme activity; with C677T the reduction is more marked in laboratory studies, especially when both copies of the gene carry the variant. Genetic analysis requires a blood draw at the practice.

What the enzyme MTHFR does in folate metabolism

Folate from food and folic acid are first converted in the cells into tetrahydrofolate, which takes up and passes on one-carbon building blocks. Part of it becomes 5,10-methylenetetrahydrofolate – and here MTHFR stands at a fork in the road: with the help of FAD, the active form of vitamin B2, and NADPH, the enzyme irreversibly converts this substance into 5-methyltetrahydrofolate. This passes its methyl group to homocysteine via methionine synthase, which needs vitamin B12; this produces methionine and from it S-adenosylmethionine (SAMe), the body's most important methyl group donor. When plenty of SAMe is present, it slows MTHFR itself – so the cycle regulates itself according to need.

What does the MTHFR C677T variant mean for metabolism?

In C677T one building block of the gene is exchanged, so that the enzyme has valine instead of alanine at position 222. This makes the enzyme heat-sensitive and it loses its FAD more easily; it works more slowly, more markedly when both copies of the gene carry the variant (TT) than with one copy (CT). Less 5-methyltetrahydrofolate is then formed, homocysteine is converted back into methionine more slowly and can rise in the blood. In studies this rise was seen mainly when little folate or vitamin B2 was available at the same time; with good supply, homocysteine in TT carriers was often within the usual range. How common the variant is differs greatly between regions and population groups.

What does the MTHFR A1298C variant mean for metabolism?

In A1298C, glutamate is exchanged for alanine at position 429 of the enzyme. This site lies in the regulatory part of the enzyme, not where FAD is bound; the enzyme remains heat-stable, and in laboratory studies its activity falls less than with C677T. On its own, A1298C usually does not lead to raised homocysteine in studies. When the two copies of the gene each carry a different variant – one C677T, one A1298C – the enzyme behaved in studies similarly to one copy of C677T or somewhat more slowly. The variants therefore change metabolism to different degrees, and the consequences depend strongly on the supply of the vitamins involved.

What happens when MTHFR forms less methylfolate?

When MTHFR works more slowly, more 5,10-methylenetetrahydrofolate remains in the cycle. This can also be an advantage: it is needed to form thymidine, a building block of DNA, and in studies a lower risk of bowel cancer was observed in TT carriers with good folate supply, which is explained by this better availability for DNA synthesis. On the other hand, less methylfolate is available for converting homocysteine back, and less SAMe is formed for methylation – for example on DNA, in building phosphatidylcholine for cell membranes, in forming creatine and in converting messenger substances. The role the variants play in individual diseases is assessed inconsistently in studies.

The interpretation is given in your report.