Methylene-tetra-hydro-folate-Reductase (MTHFR) Mutation

MTHFR stands for Methylene-Tetra-Hydro-Folate-Reductase which is a key enzyme involved in amino acid metabolism of the body. It catalyzes the conversion of 5, 10-methylenetetrahydrofolate to 5 methyltetrahydrofolate, a cosubstrate for multistep process in the conversion of the amino acid homocysteine to amino acid methionine which is then used to make proteins and other important compounds. [1] When there are genetic mutations (mostly single amino acid substitutions) occurred in the MTHFR gene, inhibiting the production of this enzyme, it may result in excess homocysteine level (hyperhomocytenemia) in blood plasma which is thought to be the susceptibility of health problems (occlusive vascular disease, neural tube defects, colon cancer, acute leukemia, methylenetetrahydrofolate deficiency) associated with homocystinuria.[2]


About 24 mutations in the MTHR gene have been identified in people with homocystinuria. Within 24 mutations, there are two variants, C677T and A1298C single nucleotide polymorphisms (SNP), are relatively common in many populations worldwide. The C677 variant nucleotide replaces cytosine with the thymine at position 677 in the MTHR gene which alters methylenetetrahydrofolate reductase and reduces its activity at higher temperatures (thermolabile) resulting in elevated levels of homocysteine in blood and homocystinuria associated health problems. [3] The A1298C variant causes a Glutamate (E) to Alanine (A) exchange at position 1298 of the MTHR and with the Alanin-containin enzyme being less active results in homocystinuria associated health problems as well. [4]

The diagnosis of deficiency in MTHFR can be simply done by applying a test of homocysteine concentrations in plasma from either whole blood samples or measurement of total homocysteine in cell free amniotic fluid through conventional chromatography or more recently using radioenzymatic method. Then specific activity level of MTHFR is determined using a direct assay of fibroblasts and/or blood cells once the homocysteine levels are identified as elevated. These non-molecular tests are not satisfying enough as they don’t allow to the genotypic identification. [5]

Annotated Bibliography

1) Goyette, Sumner, Milos, et al., Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification, Nature Genetics, 1994. 7(2): p.195-200

2) Genetic home reference, NIH Resources, MTHFR,   January 2008

3) Sibani S, Christensen B, O’Ferrall E, Saadi I, Hiou-Tim F, Rosenblatt DS, Rozen R (2000). “Characterization of six novel mutations in the methylenetetrahydrofolate reductase (MTHFR) gene in patients with homocystinuria”. Hum. Mutat. 15 (3): 280–7.

4) Yamada K, Chen Z, Rozen R, Matthews RG (December 2001). “Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase”. Proc. Natl. Acad. Sci. U.S.A. 98 (26): 14853–8

5) Ogier de Baulny, Gérard Zittoun, Remethylation defects: guidelines for clinical diagnosis and treatment. European Journal of Pediatrics, 1998, 157(14): p.77-83

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