Cytogenetic Location: 1p36.3
Molecular Location on chromosome 1: base pairs 11,769,246 to 11,788,568
The MTHFR gene provides instructions for making an enzyme called methylenetetrahydrofolate reductase. This enzyme plays a role in processing amino acids (the building blocks of proteins). Methylenetetrahydrofolate reductase is important for a chemical reaction involving forms of the vitamin folate, which is also called folic acid or vitamin B9. Specifically, this enzyme converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. This reaction is required for the multistep process that converts the amino acid homocysteine to another amino acid, methionine. The body uses methionine to make proteins and other important compounds.
A variant of this enzyme, which is called "thermolabile MTHFR" or C677T/MTHFR is due to a single mutation of the MTHFR gene. This variant does not metabolize homocysteine as well as the normal MTHFR enzyme, and blood homocysteine levels in individuals with this variant enzyme may therefore be slightly higher than in individuals with the normal enzyme.
The MTHFR mutation is extremely common:
- 44% of the population have the normal enzyme
- 44 % are heterozygous for the mutation (i.e. have 1 variant gene). These individuals have some normal enzyme and some of the thermolabile variant of the enzyme.
- 12 % are homozygous for the mutation (i.e. have 2 variant genes). All of these individuals' enzyme is the thermolabile variant.
Polymorphisms have been linked to hyperhomocysteinemia (high blood homocysteine levels). Various mutations can cause the genetic disorder homocystinuria.
At least 24 mutations in the MTHFR gene have been identified in people with homocystinuria. Most of these mutations substitute one amino acid for another amino acid in methylenetetrahydrofolate reductase. These substitutions disrupt the function of the enzyme, and may inactivate it completely. Other mutations lead to the production of an abnormally small, nonfunctional version of the enzyme. Without methylenetetrahydrofolate reductase, homocysteine cannot be converted to methionine. As a result, homocysteine builds up in the bloodstream and methionine is depleted. Some of the excess homocysteine is excreted in urine. Researchers have not determined how altered levels of homocysteine and methionine lead to the health problems associated with homocystinuria.
A specific version (variant) of the MTHFR gene may increase the risk of cardiovascular disease and certain kinds of birth defects. This variant is relatively common in many populations worldwide. It replaces the nucleotide cytosine with thymine at position 677 in the MTHFR gene, written as C677T. (Nucleotides are the building blocks of DNA.) This change in the MTHFR gene produces a form of methylenetetrahydrofolate reductase that has reduced activity at higher temperatures (thermolabile). People with the thermolabile form of the enzyme have increased levels of homocysteine in their blood.
The C677T variant has been associated with an increased risk of cardiovascular disease, including coronary heart disease and stroke, in adults. It may also play a role in the risk of high blood pressure in pregnancy (preeclampsia). Additionally, research suggests that the variant may be a risk factor for birth defects that occur during the development of the brain and spinal cord (neural tube defects). Many factors, however, play a part in determining the risk of these complex disorders.