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The Science of MTHFR “Mutations” Explained

MTHFR Mutations

For a new podcast episode on this subject, take a look at our recent discussion on The Latest Science on MTHFR.

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.

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,2 various neurological issues 3 and potential issues with birth defects.4

The 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].

MTHFR and health risks

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 B2.56 The ‘C’ allele of rs1801131 also reduces the enzyme activity of MTHFR although to a lesser extent, and the mechanism remains unknown.7

MTHFR and high homocysteine

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,8 various neurological issues9 and poor bone health10 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.11

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. However, before you start any supplement regimen, check with your doctor and read this post on B vitamin supplements and cancer risk.

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.1415

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 common “mutations” can lead to a reduction in its activity.

Both of the most common 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.

Dr. Aaron Gardner, BSc, MRes, PhD

Dr. Aaron Gardner, BSc, MRes, PhD is a life-scientist with a strong background in genetics and medical research, and the developing fields of personalized medicine and nutrition. Read his full bio here.

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