What is MTHFR? It’s Methylenetetrahydrofolate Reductase, of course!

what-is-mthfrMTHFR is a key regulatory enzyme in the metabolism of folate. It also refers to a specific gene that plays a major role in the body’s methylation process. Both the enzyme and the gene have the same name, MTHFR. The gene’s role is very complex, and recent discoveries of the Human Genome Project have been focused around the MTHFR gene polymorphisms (or variants). These polymorphisms are often referred to as ‘mutations’ or ‘defects’ because of the problems they cause in the body. Most often, when you hear someone talk about MTHFR, the person is actually referring to one of the two common MTHFR gene mutations that causes this MTHFR enzyme to become imperfect and therefore much less effective.

To put it simply, MTHFR most often refers to a genetic mutation that inhibits the ability of the body to methylate (or convert folic acid from the food we eat into the enzyme we need, L-5-Methyltetrahydrofolate  [or L-MTHF for short]). Methylfolate (L-MTHF) is most often referred to as the ‘active’ or usable form of folate that our cells require. Because the body’s cells cannot actually use folic acid, it must first go through a metabolic pathway or 4-step conversion process to become Methylfolate (L-MTHF) before the cells can directly use it (see MTHFR and Methylation). It is this metabolic pathway that the MTHFR gene defect inhibits!  See diagram on folic acid conversion steps.

Many of the learnings about this gene defect have come out of the Human Genome project and taught us that there are as many as 50+ variants of the MTHFR gene. However, only two are considered ‘common’ defects that today’s MTHFR Blood Test checks for, those  are:  677 and 1298 (discovered in 1995 and 2001 respectively). Check the FAQ to learn more about being tested for MTHFR.

Since, we all get one copy of the MTHFR gene from each parent, a person could have any one of the following combinations as well as the problems that go with it:

AA1298 / CC677 Normal for the two common variants, or mutations, 677 and 1298
AA1298 / C677T Single 677 mutation – More susceptible to environmental damage, depression, central nervous system issues, etc. (referred to as Heterozygous)
A1298C / CC677 Single 1298 mutation – More susceptible to environmental damage, depression, central nervous system issues, etc. (referred to as Heterozygous)
1298CC / CC677 Double 1298 mutation – Much worse for the above problems (referred to as Homozygous)
AA1298 / 677TT Double 677 mutation – Similar to 1298CC plus heart disease, blood clots, and more (referred to as Homozygous)
C677T / A1298C Single 1298 + Single 677 – Susceptible to all of the above and worse for strokes, heart disease, blood clots, etc. (referred to as Compound Heterozygous)


Interpreting 23andme results

MTHFR AA1298 (rs1801131) or TT is normal (no gene mutation)
MTHFR A1298C (rs1801131) or GT is heterozygous (single gene mutation)
MTHFR 1298CC (rs1801131) or GG is homozygous (a double gene mutation)
MTHFR CC677 (rs1801133) or GG is normal (no gene mutation)
MTHFR C677T (rs1801133) or AG is heterozygous (single gene mutation)
MTHFR 677TT (rs1801133) or AA is homozygous (a double gene mutation)
MTHFR A1298C (rs1801131) or GT + MTHFR C677T (rs1801133) or AG is referred to as “compound heterozygous” (a single gene mutation of each type)

And it’s very rare, but some folks can even have 3 mutations (a double mutation in one gene and a single mutation on the other) or conceivably 4 mutations (though I’ve not heard of any specific case of this in real life) if they have:

MTHFR 1298CC (rs1801131) or GG    +    MTHFR C677T (rs1801133) or AG   –   (a triple mutation)
MTHFR A1298C (rs1801131) or GT    +    MTHFR 677TT (rs1801133) or AA   –   (a triple mutation)
MTHFR 1298CC (rs1801131) or GG    +    MTHFR 677TT (rs1801133) or AA   –   (a quadruple mutation)



Normal means the MTHFR gene has neither the 677 nor the 1298 variant (defect), so it could prove to actually be ‘Normal’ or it could be one or more of the 48+ other variants there is no typical medical test for yet (though it’s worth noting that 23andme will actually test for a number of MTHFR genes, not just the 677 & 1298). If a test comes back ‘Normal’ or negative for the two well-known mutations (677 &1298), it does not necessarily mean that the body’s methylation process is working well. See MTHFR and Methylation.

What happens if the cells don't get enough active folate (L-5-MTHF) to keep the body healthy?

Find out more