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Genetics Home Reference: your guide to understanding genetic conditions
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MTHFR

Reviewed November 2014

What is the official name of the MTHFR gene?

The official name of this gene is “methylenetetrahydrofolate reductase (NAD(P)H).”

MTHFR is the gene's official symbol. The MTHFR gene is also known by other names, listed below.

What is the normal function of the MTHFR gene?

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 (also called vitamin B9). Specifically, this enzyme converts a molecule called 5,10-methylenetetrahydrofolate to a molecule called 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.

How are changes in the MTHFR gene related to health conditions?

homocystinuria - caused by mutations in the MTHFR gene

At least 40 mutations in the MTHFR gene have been identified in people with homocystinuria, a disorder in which the body is unable to process certain amino acids properly. Most of these mutations change single amino acids in methylenetetrahydrofolate reductase. These changes impair the function of the enzyme, and some cause the enzyme to be turned off (inactivated). Other mutations lead to the production of an abnormally small, nonfunctional version of the enzyme. Without functional methylenetetrahydrofolate reductase, homocysteine cannot be converted to methionine. As a result, homocysteine builds up in the bloodstream, and the amount of methionine is reduced. Some of the excess homocysteine is excreted in urine. Researchers have not determined how altered levels of homocysteine and methionine lead to the various health problems affecting multiple parts of the body in people with homocystinuria.

anencephaly - associated with the MTHFR gene

Several variations (polymorphisms) in the MTHFR gene have been associated with an increased risk of neural tube defects, a group of birth defects that occur during the development of the brain and spinal cord. Anencephaly is one of the most common types of neural tube defect. Affected individuals are missing large parts of the brain and have missing or incompletely formed skull bones.

The most well-studied polymorphism related to neural tube defects changes a single DNA building block (nucleotide) in the MTHFR gene. Specifically, it replaces the nucleotide cytosine with the nucleotide thymine at position 677 (written as 677C>T). This common variant results in a form of methylenetetrahydrofolate reductase that has reduced activity at higher temperatures (thermolabile). People with the 677C>T polymorphism, particularly those with two copies of the genetic change, have elevated levels of homocysteine in their blood resulting from the reduced activity of methylenetetrahydrofolate reductase.

Researchers have studied MTHFR gene polymorphisms in individuals with neural tube defects and in their mothers, but it remains unclear how these variations could affect the developing brain and spinal cord. The increased risk of neural tube defects may be related to differences in the ability of methylenetetrahydrofolate reductase to process folate; a shortage of this vitamin is an established risk factor for neural tube defects.

Although MTHFR gene polymorphisms are associated with an increased risk of neural tube defects, these variations are common in many populations worldwide. Most people with MTHFR gene polymorphisms do not have neural tube defects, and their children are also typically unaffected. Changes in the MTHFR gene are only one of many genetic and environmental factors that are thought to contribute to these complex conditions.

spina bifida - associated with the MTHFR gene

Polymorphisms in the MTHFR gene are also associated with an increased risk of spina bifida, another common type of neural tube defect. In people with this condition, when the spine forms, the bones of the spinal column do not close completely around the developing nerves of the spinal cord. As a result, part of the spinal cord may stick out through an opening in the spine, leading to permanent nerve damage.

As described above, variations in the MTHFR gene may increase the risk of neural tube defects by changing the ability of methylenetetrahydrofolate reductase to process folate. However, these variations are common in many populations worldwide. Most people with MTHFR gene polymorphisms do not have neural tube defects, nor do their children.

other disorders - increased risk from variations of the MTHFR gene

Polymorphisms in the MTHFR gene have also been studied as possible risk factors for a variety of common conditions. These include heart disease, stroke, high blood pressure (hypertension), high blood pressure during pregnancy (preeclampsia), an eye disorder called glaucoma, psychiatric disorders, and certain types of cancer. The 677C>T polymorphism in the MTHFR gene has also been suggested as a risk factor for cleft lip and palate, a birth defect in which there is a split in the upper lip and an opening in the roof of the mouth. Studies of MTHFR gene variations in people with these disorders have had mixed results, with associations found in some studies but not in others. Therefore, it remains unclear what role changes in the MTHFR gene play in these disorders. A large number of genetic and environmental factors, most of which remain unknown, likely determine the risk of developing most common, complex conditions.

Where is the MTHFR gene located?

Cytogenetic Location: 1p36.3

Molecular Location on chromosome 1: base pairs 11,785,729 to 11,806,102

The MTHFR gene is located on the short (p) arm of chromosome 1 at position 36.3.

The MTHFR gene is located on the short (p) arm of chromosome 1 at position 36.3.

More precisely, the MTHFR gene is located from base pair 11,785,729 to base pair 11,806,102 on chromosome 1.

See How do geneticists indicate the location of a gene? (http://ghr.nlm.nih.gov/handbook/howgeneswork/genelocation) in the Handbook.

Where can I find additional information about MTHFR?

You and your healthcare professional may find the following resources about MTHFR helpful.

You may also be interested in these resources, which are designed for genetics professionals and researchers.

What other names do people use for the MTHFR gene or gene products?

  • 5,10-methylenetetrahydrofolate reductase (NADPH)
  • methylenetetrahydrofolate reductase
  • MTHR_HUMAN

See How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What glossary definitions help with understanding MTHFR?

acids ; amino acid ; birth defect ; cancer ; cytosine ; DNA ; enzyme ; folate ; gene ; glaucoma ; hypertension ; methionine ; molecule ; neural tube defects ; nucleotide ; palate ; polymorphism ; risk factors ; thermolabile ; thymine

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Botto LD, Yang Q. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol. 2000 May 1;151(9):862-77. Review. (http://www.ncbi.nlm.nih.gov/pubmed/10791559?dopt=Abstract)
  • Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG; MTHFR Studies Collaboration Group. MTHFR 677C-->T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA. 2002 Oct 23-30;288(16):2023-31. (http://www.ncbi.nlm.nih.gov/pubmed/12387655?dopt=Abstract)
  • NCBI Gene (http://www.ncbi.nlm.nih.gov/gene/4524)
  • Sibani S, Christensen B, O'Ferrall E, Saadi I, Hiou-Tim F, Rosenblatt DS, Rozen R. Characterization of six novel mutations in the methylenetetrahydrofolate reductase (MTHFR) gene in patients with homocystinuria. Hum Mutat. 2000;15(3):280-7. (http://www.ncbi.nlm.nih.gov/pubmed/10679944?dopt=Abstract)
  • Trabetti E. Homocysteine, MTHFR gene polymorphisms, and cardio-cerebrovascular risk. J Appl Genet. 2008;49(3):267-82. doi: 10.1007/BF03195624. Review. (http://www.ncbi.nlm.nih.gov/pubmed/18670064?dopt=Abstract)
  • Trimmer EE. Methylenetetrahydrofolate reductase: biochemical characterization and medical significance. Curr Pharm Des. 2013;19(14):2574-93. Review. (http://www.ncbi.nlm.nih.gov/pubmed/23116396?dopt=Abstract)
  • Urreizti R, Moya-García AA, Pino-Ángeles A, Cozar M, Langkilde A, Fanhoe U, Esteves C, Arribas J, Vilaseca MA, Pérez-Dueñas B, Pineda M, González V, Artuch R, Baldellou A, Vilarinho L, Fowler B, Ribes A, Sánchez-Jiménez F, Grinberg D, Balcells S. Molecular characterization of five patients with homocystinuria due to severe methylenetetrahydrofolate reductase deficiency. Clin Genet. 2010 Nov;78(5):441-8. doi: 10.1111/j.1399-0004.2010.01391.x. (http://www.ncbi.nlm.nih.gov/pubmed/20236116?dopt=Abstract)
  • Yadav U, Kumar P, Yadav SK, Mishra OP, Rai V. "Polymorphisms in folate metabolism genes as maternal risk factor for neural tube defects: an updated meta-analysis". Metab Brain Dis. 2014 Jul 9. [Epub ahead of print]. (http://www.ncbi.nlm.nih.gov/pubmed/25005003?dopt=Abstract)
  • Yan L, Zhao L, Long Y, Zou P, Ji G, Gu A, Zhao P. Association of the maternal MTHFR C677T polymorphism with susceptibility to neural tube defects in offsprings: evidence from 25 case-control studies. PLoS One. 2012;7(10):e41689. doi: 10.1371/journal.pone.0041689. Epub 2012 Oct 3. (http://www.ncbi.nlm.nih.gov/pubmed/23056169?dopt=Abstract)
  • Zhang T, Lou J, Zhong R, Wu J, Zou L, Sun Y, Lu X, Liu L, Miao X, Xiong G. Genetic variants in the folate pathway and the risk of neural tube defects: a meta-analysis of the published literature. PLoS One. 2013 Apr 4;8(4):e59570. doi: 10.1371/journal.pone.0059570. Print 2013. (http://www.ncbi.nlm.nih.gov/pubmed/23593147?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: November 2014
Published: November 24, 2014