What is the Effect of the MTHFR Gene Mutation in Humans

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What is the MTHFR gene?

The full name of the MTHFR gene is “methylenetetrahydrofolate reductase (NAD(P)H).” The protein encoded by this gene is an enzyme that catalyzes the reduction of methylenetetrahydrofolate to methyltetrahydrofolate, “a cofactor for homocysteine methylation to methionine” (Goyette et al., 1994). This enzyme is essential for the homeostasis and normal metabolism of intracellular folate.

In humans, MTHFR is located on the chromosome 1. It is expressed in various tissues including the brain, muscle, liver, and stomach (Gaughan et al., 2000). MTHFR gene mutation can cause methylenetetrahydrofolate reductase deficiency. Genetic variations in this gene have been related to many diseases including colon cancer, leukemia, vascular disease, depression, schizophrenia, migraine with aura, glaucoma, Down syndrome, and neural tube defects.

MTHFR gene mutation and diseases

Different types of mutations have been found in the MTHFR gene, including missense and nonsense mutations (Goyette et al., 1994). MTHFR gene mutations may cause the deficiency of the protein, which has been related to diseases such as homocystinuria, an inherited disorder with the abnormal metabolism of the amino acid methionine. The symptoms of homocystinuria include delayed development, visual problems, long limbs, and psychiatric disorders.

A common gene mutation may occur at the nucleotide number 677, with a C-to-T substitution. The mutation converts the alanine to a valine residue. Such a mutation may lead to the synthesis of a thermolabile form of the protein (Frosst et al., 1995), i.e., its decomposition in response to heat.

In patients with low folate status, this 677C-T mutation has been connected to hyperhomocysteinemia that has high levels of homocysteine in the blood (Guttormsen et al., 1996). It is a problem that may show symptoms of general pain and inflammation, with the increased risk of heart disease. The hyperhomocysteinemia patients often also have reduced intake of vitamins, consume more coffee, and smoke frequently. This is caused by a mutation that prohibts the body from converting folate into usable Methylfolate (L-MTHF). One possible treatment is for patients with this condition to take L-MTHF (or 5-MTHF).

This MTHFR gene mutation (677C-T) has been considered a critical risk factor in vascular disease. For example, a study of 362 Japanese male patients found the association between this mutation and coronary artery disease (CAD) (Morita et al., 1997). The mutation may cause impaired folate metabolism, which leads to the elevation of plasma homocystine levels and the increased risk of coronary heart disease (Klerk et al., 2002). In addition, this mutation has been suggested a risk factor for hypertension (Qian et al., 2007).

MTHFR and cancer treatment

MTHFR gene mutations play significant roles in the investigation of cancer treatment. This is because of their close relationships with the intracellular folate composition and one-carbon transfer reactions (Kim, 2009). Specifically, the MTHFR 677C-T mutation has been associated with cancer risks. The combination of this mutation with low folate levels may be related to abnormal DNA methylation, a common feature of human neoplasia (Castro et al., 2004).

Furthermore, genetic variations in the MTHFR gene have been connected with the responses to chemotherapeutic drugs such as 5-fluorouracil (5FU) and methotrexate (MTX) (Kim, 2009). These drugs are commonly used for cancer treatments and for anti-inflammatory effects. In fact, MTHFR inhibition has been suggested as a potential target for improving the effects of 5FU-based chemotherapy.


Castro, R., Rivera, I., et al. (2004) 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C–>T and 1298A–>C mutations are associated with DNA hypomethylation. J Med Genet 41, 454-458.

Frosst, P., Blom, H. J., et al. (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10, 111-113.

Gaughan, D. J., Barbaux, S., et al. (2000) The human and mouse methylenetetrahydrofolate reductase (MTHFR) genes: genomic organization, mRNA structure and linkage to the CLCN6 gene. Gene 257, 279-289.

Goyette, P., Sumner, J. S., et al. (1994) Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat Genet 7, 195-200.

Guttormsen, A. B., Ueland, P. M., et al. (1996) Determinants and vitamin responsiveness of intermediate hyperhomocysteinemia (> or = 40 micromol/liter). The Hordaland Homocysteine Study. J Clin Invest 98, 2174-2183.

Kim, Y. I. (2009) Role of the MTHFR polymorphisms in cancer risk modification and treatment. Future Oncol 5, 523-542.

Klerk, M., Verhoef, P., et al. (2002) MTHFR 677C–>T polymorphism and risk of coronary heart disease: a meta-analysis. Jama 288, 2023-2031.

Morita, H., Taguchi, J., et al. (1997) Genetic polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) as a risk factor for coronary artery disease. Circulation 95, 2032-2036.

Qian, X., Lu, Z., et al. (2007) A meta-analysis of association between C677T polymorphism in the methylenetetrahydrofolate reductase gene and hypertension. Eur J Hum Genet 15, 1239-1245.

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