Unaffected By The MTHFR Polymorphism

Methyltetrahydrofolate Reductase (MTHFR) is one of the enzymes involved in folate metabolism. As highlighted in the chart below, MTHFR play a central role in converting 5,10 MTHF to L-methylfolate.

Folic Acid Must Complete a 4 Step Conversion Process

As the chart above indicates, it takes four biochemical reactions for your body to convert supplemental folic acid into L-methylfolate:

1. In the process of intestinal absorption and subsequent transfer into peripheral tissue, folic acid is converted into Dihydrofolate (DHF) by the Dihydrofolate Reductase enzyme (DHFR).
2. DHF is then metabolized into Tetrahydrofolate (THF) again by DHFR.
3. THF is metabolized into 5,10-Methylene-THF.
4. 5,10-Methylene-THF is converted to L-methylfolate by the Methyltetrahydrofolate Reductase enzyme (MTHFR).

What is a MTHFR 677 C→T Polymorphism?

Most genes in the body are present in two forms or "alleles": one from the father and one from the mother. The two alleles of a gene could have the exact same composition, or they could be different. Sometimes these differences are due to a "mutation" which results in a change of composition. If a mutation in a gene is common and is seen often throughout the population, it is referred to as a "Polymorphism". The C677T mutation in the MTHFR gene is a Polymorphic mutation.

The C677T mutation or MTHFR 677 C→T Polymorphism is characterizedby a mutation at the 677 base position where a cytosine base is replaced by a thymine. This substitution occurs at a site which is critical for the enzyme activity and leads to the coding of a less active enzyme due to the replacement of a single amino acid alanine by a second amino acid, valine.

Individuals with this polymorphism have been shown to have an elevation of homocysteine concentrations of approximately 20%.

What is a MTHFR C677T Genotype?

The MTHFR genotype refers to the specific genetic makeup of the MTHFR gene. Individuals can be divided into three categories based on their MTHFR genotype (see chart):

(C/C)

Those whose alleles have the normal base (cytosine) at position 677 (CC or normal MTHFR C677T genotype).

(C/T)

Those who have one allele with the normal base (cytosine) at position 677 and one allele in which the cytosine was replaced by thymine (CT, or heterozygotes for the C677T mutation).

(T/T)

Those who have both alleles where the 677 positions are occupied by thymine (TT, or homozygotes for the C677T mutation).

What is the relationship between MTHFR genotype and enzyme activity?

The replacement of the amino acid alanine by the amino acid valine will result in a less active enzyme. In patients with the C/T genotype, the enzyme is only 71% as active as the normal C/C enzyme, while in patients with the most severe form, T/T genotype, the enzyme is only 34% as active.⁷

Genotype	% Residual Enzyme Activity
C/C	100
C/T	71
T/T	34

Individuals with the MTHFR 677 C→T Polymorphism have a reduced specific enzymatic activity of the MTHFR gene. The presence of a T allele may result in higher homocysteine levels and a lower plasma folate concentration, which is more pronounced in the T/T subjects.

In the general population the allelic frequency of the C/T mutation is about 40 to 50%. In some studies, the frequency of the T/T mutation has been shown to be about 10 to 12 %.

Prevalence of the MTHFR C→T Polymorphism by Genotype

A common MTHFR C→T Polymorphism exists affecting approximately 40 to 50% of the population.^1,4,5

Individuals with the C677T Polymorphism have reduced MTHFR enzyme activity resulting in an elevation of homocysteine levels by approximately 20%.⁶