methylenetetrahydrofolate reductase
Normal Function
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 the vitamin folate (also called vitamin B9). Specifically, this enzyme converts a form of folate called 5,10-methylenetetrahydrofolate to a different form of folate called 5-methyltetrahydrofolate. This is the primary form of folate found in blood, and is necessary for the multistep process that converts the amino acid hom*ocysteine to another amino acid, methionine. The body uses methionine to make proteins and other important compounds.
Health Conditions Related to Genetic Changes
hom*ocystinuria
At least 40 mutations in the MTHFR gene have been identified in people with hom*ocystinuria, a disorder in which the body is unable to process hom*ocysteine and methionine properly. People with this condition often develop eye problems, abnormal blood clotting, skeletal abnormalities, and learning problems. Most of the mutations that cause hom*ocystinuria 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, hom*ocysteine cannot be converted to methionine. As a result, hom*ocysteine builds up in the bloodstream, and the amount of methionine is reduced. Some of the excess hom*ocysteine is excreted in urine (hom*ocystinuria). Researchers have not determined how altered levels of hom*ocysteine and methionine lead to the various health problems affecting multiple parts of the body in people with hom*ocystinuria.
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Age-related hearing loss
MedlinePlus Genetics provides information about Age-related hearing loss
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Alopecia areata
MedlinePlus Genetics provides information about Alopecia areata
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Anencephaly
Some studies have found that variations (polymorphisms) in the MTHFR gene have been associated with a small 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 MTHFR polymorphism 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 (the enzyme is thermolabile). People with the 677C>T polymorphism, particularly those with the genetic change in both copies of the gene, have elevated levels of hom*ocysteine in their blood (hyperhom*ocysteinemia) resulting from the reduced activity of methylenetetrahydrofolate reductase.
Researchers have studied MTHFR gene polymorphisms and hyperhom*ocysteinemia in individuals with neural tube defects and in their mothers, but it remains unclear how these variations affect the developing brain and spinal cord. The association with neural tube defects may be related to differences in the ability of methylenetetrahydrofolate reductase to process folate. While a shortage (deficiency) of this vitamin is an established risk factor for neural tube defects, there are many factors that can contribute to folate deficiency.
MTHFR gene polymorphisms are common worldwide, with an estimated 25 percent of Hispanics and 10 to 15 percent of North American whites having the 677C>T polymorphism in both copies of the gene. Most people with MTHFR gene polymorphisms do not have neural tube defects, and their children are also typically unaffected.
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Spina bifida
Some studies have found that polymorphisms in the MTHFR gene are also associated with a small increased risk of spina bifida, another common type of neural tube defect. When the spine forms in people with this condition, 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 generally result in hyperhom*ocysteinemia due to reduce activity of methylenetetrahydrofolate reductase and its ability to process folate. It is unclear how MTHFR gene changes might influence the development of neural tube defects. 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.
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Other disorders
Polymorphisms in the MTHFR gene can alter or decrease the activity of methylenetetrahydrofolate reductase, leading to a mild increase of hom*ocysteine in the blood (hyperhom*ocysteinemia). The two MTHFR gene polymorphisms that are the most common and the most frequently studied are 677C>T and a change that replaces the nucleotide adenosine with the nucleotide cytosine at position 1298 (written as 1298A>C).
An increase in hom*ocysteine levels caused by MTHFR gene polymorphisms have been studied as possible risk factors for a variety of common conditions. These include high blood pressure (hypertension), blood clots, pregnancy loss, psychiatric disorders, and certain types of cancer. Research indicates that individuals who have the 677C>T polymorphism on both copies of the MTHFR gene have an increased risk of developing vascular disease, including heart disease and stroke. The 677C>T polymorphism 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, the role that changes in the MTHFR gene play in these disorders remains unclear. It is likely that additional factors influence the processing of hom*ocysteine and that variations in hom*ocysteine levels play a role in whether a person develops any of these conditions. A large number of genetic and environmental factors, most of which remain unknown, likely determine the risk of developing most common complex conditions.
Other Names for This Gene
- 5,10-methylenetetrahydrofolate reductase
- 5,10-methylenetetrahydrofolate reductase (NADPH)
- methylenetetrahydrofolate reductase (NAD(P)H)
- MTHR_HUMAN
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
References
- ACOG Practice Bulletin No. 197 Summary: Inherited Thrombophilias inPregnancy. Obstet Gynecol. 2018 Jul;132(1):249-251. doi:10.1097/AOG.0000000000002705. Citation on PubMed
- Bhargava S, Ali A, Parakh R, Saxena R, Srivastava LM. Higher incidence ofC677T polymorphism of the MTHFR gene in North Indian patients with vasculardisease. Vascular. 2012 Apr;20(2):88-95. doi: 10.1258/vasc.2011.oa0320. Epub 2012Feb 28. Citation on PubMed
- Botto LD, Yang Q. 5,10-Methylenetetrahydrofolate reductase gene variants andcongenital anomalies: a HuGE review. Am J Epidemiol. 2000 May 1;151(9):862-77.doi: 10.1093/oxfordjournals.aje.a010290. Citation on PubMed
- Hickey SE, Curry CJ, Toriello HV. ACMG Practice Guideline: lack of evidencefor MTHFR polymorphism testing. Genet Med. 2013 Feb;15(2):153-6. doi:10.1038/gim.2012.165. Epub 2013 Jan 3. Erratum In: Genet Med. 2020Dec;22(12):2125. doi: 10.1038/s41436-020-0843-0. Citation on PubMed
- Khandanpour N, Willis G, Meyer FJ, Armon MP, Loke YK, Wright AJ, Finglas PM,Jennings BA. Peripheral arterial disease and methylenetetrahydrofolate reductase(MTHFR) C677T mutations: A case-control study and meta-analysis. J Vasc Surg.2009 Mar;49(3):711-8. doi: 10.1016/j.jvs.2008.10.004. Epub 2009 Jan 21. Citation on PubMed
- Kumar A, Kumar P, Prasad M, Sagar R, Yadav AK, Pandit AK, Jali VP, Pathak A.Association of C677T polymorphism in the methylenetetrahydrofolate reductase gene(MTHFR gene) with ischemic stroke: a meta-analysis. Neurol Res. 2015Jul;37(7):568-77. doi: 10.1179/1743132815Y.0000000008. Epub 2015 Jan 16. Citation on PubMed
- Levin BL, Varga E. MTHFR: Addressing Genetic Counseling Dilemmas UsingEvidence-Based Literature. J Genet Couns. 2016 Oct;25(5):901-11. doi:10.1007/s10897-016-9956-7. Epub 2016 Apr 30. Citation on PubMed
- Liu F, Silva D, Malone MV, Seetharaman K. MTHFR A1298C and C677T PolymorphismsAre Associated with Increased Risk of Venous Thromboembolism: A RetrospectiveChart Review Study. Acta Haematol. 2017;138(4):208-215. doi: 10.1159/000480447.Epub 2017 Dec 7. Citation on PubMed
- Moll S, Varga EA. hom*ocysteine and MTHFR Mutations. Circulation. 2015 Jul7;132(1):e6-9. doi: 10.1161/CIRCULATIONAHA.114.013311. No abstract available. Citation on PubMed
- Sibani S, Christensen B, O'Ferrall E, Saadi I, Hiou-Tim F, Rosenblatt DS,Rozen R. Characterization of six novel mutations in the methylenetetrahydrofolatereductase (MTHFR) gene in patients with hom*ocystinuria. Hum Mutat.2000;15(3):280-7. doi:10.1002/(SICI)1098-1004(200003)15:33.0.CO;2-I. Citation on PubMed
- Trabetti E. hom*ocysteine, MTHFR gene polymorphisms, and cardio-cerebrovascularrisk. J Appl Genet. 2008;49(3):267-82. doi: 10.1007/BF03195624. Citation on PubMed
- Trimmer EE. Methylenetetrahydrofolate reductase: biochemical characterizationand medical significance. Curr Pharm Des. 2013;19(14):2574-93. doi:10.2174/1381612811319140008. Citation on PubMed
- Urreizti R, Moya-Garcia AA, Pino-Angeles A, Cozar M, Langkilde A, Fanhoe U,Esteves C, Arribas J, Vilaseca MA, Perez-Duenas B, Pineda M, Gonzalez V, ArtuchR, Baldellou A, Vilarinho L, Fowler B, Ribes A, Sanchez-Jimenez F, Grinberg D,Balcells S. Molecular characterization of five patients with hom*ocystinuria dueto severe methylenetetrahydrofolate reductase deficiency. Clin Genet. 2010Nov;78(5):441-8. doi: 10.1111/j.1399-0004.2010.01391.x. Citation on PubMed
- Xie SZ, Liu ZZ, Yu JH, Liu L, Wang W, Xie DL, Qin JB. Association between theMTHFR C677T polymorphism and risk of cancer: evidence from 446 case-controlstudies. Tumour Biol. 2015 Nov;36(11):8953-72. doi: 10.1007/s13277-015-3648-z.Epub 2015 Jun 17. Citation on PubMed
- Yadav U, Kumar P, Yadav SK, Mishra OP, Rai V. "Polymorphisms in folatemetabolism genes as maternal risk factor for neural tube defects: an updatedmeta-analysis". Metab Brain Dis. 2015 Feb;30(1):7-24. doi:10.1007/s11011-014-9575-7. Epub 2014 Jul 9. Citation on PubMed
- Yan L, Zhao L, Long Y, Zou P, Ji G, Gu A, Zhao P. Association of the maternalMTHFR C677T polymorphism with susceptibility to neural tube defects inoffsprings: evidence from 25 case-control studies. PLoS One. 2012;7(10):e41689.doi: 10.1371/journal.pone.0041689. Epub 2012 Oct 3. Citation on PubMed or Free article on PubMed Central
- 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: ameta-analysis of the published literature. PLoS One. 2013 Apr 4;8(4):e59570. doi:10.1371/journal.pone.0059570. Print 2013. Citation on PubMed or Free article on PubMed Central
