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The science of MTHFR mutations explained

MTHFR Mutations

If you’re interested in personalized genetic medicine you will have undoubtedly come across the protein methylenetetrahydrofolate reductase (MTHFR). MTHFR is an enzyme which is encoded by the MTHFR gene and functions to convert 5,10-methylenetetrahydrofolate (MeTHF) to 5-methlytetrahydrofolate (MTHF). What sounds like a pretty un-inspiring reaction has actually become one of, if not the, most investigated reactions in the field of personalized genetic medicine. This is due to its association with several disorders including heart disease [1], stroke [2], high blood pressure [3], various neurological issues [4] and potential issues with birth defects [5].

One carbon pathway

MTHFR actually sits in the middle of a rather complicated pathway, called the one carbon pathway, which is involved in the conversion of dietary folate into a variety of other products which are key in the synthesis of DNA, RNA and amino acids, so it’s pretty fundamental to life.

Two polymorphisms in MTHFR have been identified which lead to a reduction in enzyme activity; rs1801133 (C677T) and rs1801131 (A1298C) which are detailed in the table below.

ProteinGeneSNP IDMajor Allele/Minor Allele (Risk)Risk
C/TC (Ala) > T (Val) leads to a heat-sensitive enzyme with reduced activity. Also the required co-factor vitamin B2 is released more quickly by those with the ‘T’ allele [R].
A/CA (Glu) > C (Ala) leads to a smaller reduction of enzyme activity than described above through an unknown mechanism [R].

How do MTHFR SNPs lead to poor health?

As discussed in the table above the those carrying the ‘T’ allele of the rs1801133 SNP display a reduced MTHFR enzyme activity of between 30-70%; which leads to a reduction in the conversion of 5,10-MeTHF to 5-MTHF. It is thought that this occurs because the enzyme is rendered more heat sensitive by the substitution of a valine for an alanine, and also has a reduced ability to stay bound with its co-factor, vitamin B[6,7]. The ‘C’ allele of rs1801131 also reduces the enzyme activity of MTHFR although to a lesser extent, and the mechanism remains unknown [8].

This lack of enzyme activity doesn’t directly lead to the development of the disorders listed above. Rather, it is how the lack of 5-MTHF impacts on the processing of another molecule called homocysteine, which when present at elevated levels, can be very damaging to tissue, and is associated with increased cardiovascular risks [9], various neurological issues [10] and poor bone health [11] amongst others.

Homocysteine is typically converted into methionine, or cysteine, both of which are less harmful. The major driver of this conversion is an enzyme called methionine synthase, although there are other pathways involved as well. Methionine synthase generates methionine from homocysteine using 5-MTHF as a donor for a methyl group. With a lack of  5-MTHF, as occurs in those with less functional MTHFR, this reaction stalls and leads to an accumulation of homocysteine.

The interaction between the one carbon pathway and the processing of homocysteine into less harmful products is quite confusing so I’ve made the diagram below to highlight the key enzymes involved. One very interesting thing to note is the importance of B vitamins in both the one carbon pathway and homocysteine clearance. Whilst those eating a healthy, balanced diet should receive a sufficient dietary intake of B vitamins, many of us don’t. So attempts to deal with MTHFR enzyme deficiency by supplementing with folate alone may not prove successful if the enzymes of the various pathways cannot function.

B vitamins MTHFR

Very briefly dietary folate is converted into tetrahydrofolate (THF) as an entrance point into the one carbon cycle. Serine hydroxymethyltransferase converts THF into 5,10-methylenetetrahydrofolate (5,10-MTHF) using vitamin B6 as a co-factor. 5,10-MTHF is then converted into 5-MTHF via the enzyme methylenetetrahydrofolate reductase (MTHFR), which uses vitamin B2 as a co-factor. Finally methionine synthase, which uses vitamin B12 as a co-factor uses 5-MTHF as a methyl donor to convert homocysteine into methionine, resulting in the reformation of THF.

Simultaneously the enyzme betaine homocysteine methyltransferase uses betaine as a methyl donor to convert homocysteine into methionine. Whilst two enzymes which use vitamin B6 as a co-factor convert homocysteine into cysteine. A block in the one carbon pathway as occurs in those with reduced MTHFR activity can therefore lead to an accumulation of homocysteine.

Are MTHFR SNPs really all that bad?

As numerous previous studies have proved inconclusive when assessing the role of MTHFR rs1801133 (C677T) and rs1801131 (A1298C) SNPs in relation to heart disease, a large scale meta-analysis (a large study combining the results of many smaller studies) was performed. No general association between these SNPs and increased cardiac risk was observed. However, for several subgroups namely African, North American and elderly populations a significant association was observed, with those carrying the ‘T‘ polymorphism of rs1801133 being at elevated risk of suffering a heart attack [12].

However, MTHFR C677T was observed to play a role when looking at stroke patients. There was a strong association between the ‘T‘ allele of rs1801133 and the occurrence of strokes [12]. As far as I’m aware robust meta analyses for the other disorders associated with MTHFR mutations are not available, although I will update this post as and when I find any.

What to do if you carry one of these SNPs

Well, first things first there is a simple blood test available to determine if you have high homocysteine levels.

If detected, supplementation with vitamins B2, B6, B12, methylfolate and betaine may be beneficial. Additionally, as deficiency in these vitamins is also associated with numerous other disorders, due to their important role as co-factors for numerous enzymes, general supplementation may be beneficial.

It is difficult to find studies investigating the effect of supplementation on issues such as heart health due to the timescales involved and issues with the ethics of clinical trials. However, the effect of folate supplementation for expectant mothers has been widely investigated and has been strongly linked with a reduction in birth defects [13]. The effect was so strong that in the USA and many other Western countries grains and cereals are now regularly fortified with additional folate.

This fortification sounds great on paper, however some researchers now think that it is in fact causing health issues of its own, especially in those with reduced MTHFR enzyme activity [14,15].

B vitamins MTHFR

Lets look at this diagram from above again. In a person with fully active MTHFR enzyme, the One Carbon Pathway will cycle normally. But in someone carrying either of the SNPs MTHFR rs1801133 (C677T) or rs1801131 (A1298C) this activity is reduced. As I discuss above this leads to a reduction in 5-MTHF and the accumulation of homocysteine, but also importantly the product which MTHFR should be breaking down will also build up as well. If we add an excess of folate into this system through supplementation it is easy to see how this precursor product could rapidly accumulate.

As such just increasing folate intake may not be the best process, rather taking a holistic approach and activating all parts of the pathway to encourage proper cycling may be the way forward.

Take-home message

I hope the above post has helped you understand how the MTHFR enzyme functions and how to common SNPs can lead to a reduction in its activity.

Both of these SNPs are associated with a wide variety of disorders, associations which have been reinforced by large scale meta-analyses. Although the effect of supplementation has been widely investigated in expectant mothers, the impact on other disorders, especially in those carrying either MTHFR rs1801133 (C677T) or rs1801131 (A1298C) has not.

However, a rapid, easy test for elevated homocysteine is available for those who are concerned, or those who know they carry one of the above SNPs. If levels are found to be elevated a holistic supplement containing methlyfolate and numerous B vitamins may be preferred to folate alone.

Aaron Gardner

Dr Aaron Gardner is a life-scientist with a strong background in genetics and medical research, and a particular interest in the developing fields of personalised medicine and nutrition.

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  1. Susan says:

    Thank you Aaron, really enjoy all the information you post!

    I have the C677T and PA but have low (5.6)homocysteine, methionine etc. Could it be that I’m taking too much hydroxyB12(injections) and an imbalance of other b vitamins?

    • Hi Susan, if you’re having B12 injections I’m assuming it’s quite a high dose? I would always suggest balancing your B vitamin intake and not just focusing on one, it’s quite tempting to go in with a high dose thinking about MTHFR in isolation and forgetting that it’s part of a much wider cycle.

  2. Pat says:

    I inherited two of the MTHFR genes, one from each parent. It is a shame that most doctors do not know anything about it. Sending a person to a cardiologist because of high homocysteine, and increasing statins, has not helped me. In fact statins have caused me to have memory loss.

  3. Paolo says:

    This is very well explained, thank you. I have some questions.

    Considering prevalence and activity of the enzyme MTHFR I have realized that the enzyme with 100% activity is, in fact, present in a very small percentage of the general population (16%). This seems weird to me, and could perhaps mean that a fully active MTHFR enzyme has some detrimental effect on health. Is it possible?

    Another question is: in the scenario of low MTHFR activity, could accumulation of folate, THF, and 5,10-MTHF be toxic?

    The last question; which is the best way to supplement vitamin B-12?

    Thank you so much!


    • Hi Paolo,

      I guess it’s possible that there could be negative effects associated with having full MTHFR function, but I’ve not read anything about it. For those with low activity as associated with the C677T the accumulation of other substrates may have some impact on the body but likely only a negligible one. As for B vitamin supplementation, I would have a read of this:

      Then if you decide to supplement your diet a good pan-B-vitamin supplement is often the best course.

  4. Aaron, great post as usual. So, to simplify some of the science here for the readers, those with MTHFR mutations C677T, and A1298C typically have a reduced ability to metabolize folate, and folic acid, into usable “methyl” forms of those nutrients, and it’s the methyl forms of those nutrients that, through methylation pathways, break down homocysteine and turn it into methionine? As a result, MTHFR mutations can result in elevated homocysteine levels, and it’s really the homocysteine, more so than the MTHFR, that has been associated with disease?

    • Aaron Gardner says:

      Thanks John! Yes that’s exactly it, the C677T and A1298C MTHFR SNPs cause the MTHFR enzyme to act as a bottleneck in the processing of folate and folic acid into the methylfolate required to clear homocysteine.

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