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MTHFR - Humpath.com - Human pathology

Home > A. Molecular pathology > MTHFR


Sunday 19 March 2006

Folates are carriers of one-carbon units and are metabolized by 5,10-methylenetetrahydrofolate reductase (MTHFR) and other enzymes that use riboflavin, cobalamin, or vitamin B6 as cofactors.

These B vitamins are essential for the remethylation and transsulfuration of homocysteine, which is an important intermediate in one-carbon metabolism.

The MTHFR gene is of particular importance in the folate and homocystéine metabolic cycle as it regulates the available folate for Hcy remethylation,


- Some reports have linked a common polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene to altered DNA methylation patterns in response to diet, alcohol consumption and hormone replacement and an apparent increased incidence of breast and colorectal cancer in certain populations.

For example, the common MTHFR 677CT polymorphism has been shown to increase the risk of breast cancer up to 3-fold in premenopausal women. Other studies suggest that the 677TT genotype confers a 40% decreased risk of breast cancer, particularly in postmenopausal women using hormone replacement therapy, by limiting the availability of nucleic acid precursors required by hyperproliferating cells.

- MTHFR has been most extensively studied as a potential risk factor for neural tube defects (NTDs).

  • A common single-nucleotide polymorphism (SNP) in this gene, 677C→T, is associated with reduced levels of enzyme activity, elevated levels of plasma Hcy and an increased NTD risk in some populations.
  • Two Meta-analysis studies strongly implicate the MTHFR 677TT genotype as a risk factor for NTDs in mothers and affected children.
  • A second mutation in the MTHFR gene, 1298A→C, has been identified and found to be associated with a reduced level of enzyme activity (not as severe as with 677C→T) and an increased risk for NTDs but with no effect on Hcy plasma levels.
  • The trifunctional enzyme MTHFD plays a central role in folate metabolism as it is involved in many conversion reactions of substrates used in purine and thymidine synthesis.
  • One DNA variant in MTHFD has been identified, 1958G→A, and found to be associated with an increased NTD risk for mothers to have an NTD-affected child.

- The MTHFR 677C→T is related to decreased MTHFR activity, low plasma folate and high plasma homocysteine and has a variable penetrance affected by dietary and supplemental folate.

- The RFC-1 80A→G variant may interact with low red blood cell folate status and MTHFR mutations to increase NTDs risk.


- Kibar Z, Capra V, Gros P. Toward understanding the genetic basis of neural tube defects. Clin Genet. 2007 Apr;71(4):295-310. PMID: 17470131


- Hustad S, Midttun O, Schneede J, Vollset SE, Grotmol T, Ueland PM. The Methylenetetrahydrofolate Reductase 677C—>T Polymorphism as a Modulator of a B Vitamin Network with Major Effects on Homocysteine Metabolism. Am J Hum Genet. 2007 May;80(5):846-55. PMID: 17436239


  • Folate-homocysteine pathway
  • MTHFR mutations