MTHFR

Official Full Name

methylenetetrahydrofolate reductase

Organism

Homo sapiens

GeneID

4524

Background

The protein encoded by this gene catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Genetic variation in this gene influences susceptibility to occlusive vascular disease, neural tube defects, colon cancer and acute leukemia, and mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.[provided by RefSeq, Oct 2009]

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Detailed Information

MTHFR is a flavoprotein, and the MTHFR gene is located on chromosome 1. The gene is 2, 220 bp in length and contains 11 exons and 10 introns. MTHFR is encoded by the MTHFR gene and found to have 29 mutations in the human MTHFR gene, the most common of which is the C677T mutation. MTHFR is a key metabolic enzyme in the folate metabolic pathway and its function is to reduce 5,10-methylenetetrahydrofolate in vivo to 5-methyltetrahydrofolate. 5-Methyltetrahydrofolate is an important methyl donor involved in many biological processes (such as the synthesis of purines and pyrimidines). At the same time, MTHFR is a key metabolic enzyme for the re-methylation of homocysteine (HCY).

Figure 1. Folic acid and MTHFR. (Khorshied, M. M., et al. 2014)

MTHFR deficiency can lead to a decrease in the synthesis of 5-methyltetrahydrofolate and impediment of HCY methylation, which prevents HCY from being methylated to methionine. The physiological metabolism of HCY is at the intersection of the two metabolic pathways of remethylation and transsulfation. When the concentration of HCY in the blood is increased, it can cause vascular occlusion, endothelial damage and even blood pressure in adults. There is also a significant teratogenic effect on the heart during organogenesis. Experiments have shown a dose-response relationship, so high HCY is an important risk factor for fetal birth defects and cardiovascular disease.

MTHFR Gene Polymorphism

The MTHFR gene is a polymorphic gene with multiple mutation types. Different types of gene mutations cause MTHFR to exhibit a variety of different enzyme activities and thermal stability. When a C→T point mutation occurs at the 677th nucleotide in the fourth exon, a missense mutation is formed, that is, alanine is replaced by proline, which increases the thermal instability of MTHFR and the reduce of MTHFR activity. The MTHFR gene C677T allele has a mutation rate of 18. 6%, Asia is 20. 8%, Africa is 6. 6%, the US is 32. 2%, Australia is 4. 7%.

MTHFR C677T polymorphism results in the conversion of the 222th codon alanine (Ala) to proline (Val). Studies have shown that the homozygous (TT) genotype of the MTHFR C677T polymorphism has high plasma Hcy and low serum folate levels compared to heterozygous genotypes (CT) and wild type (CC). The MTHFR C677T polymorphism can result in a 35% reduction in a thermolabile protease activity in heterozygous genotypes. In the homozygous genotype, the activity of the enzyme is reduced by 70%, which in turn causes Hhcy to form an oxidative stress reaction, further causing sperm DNA and membrane damage. Structural analysis of MTHFR flavin protein showed that the C677T polymorphism plays an important role in the affinity change of the MTHFR-flavin adenine dinucleotide binding site, and that the C677T polymorphism can be used as a screening sterile biomarker for idiopathic males.

MTHFR and Congenital Heart Defects (CHD)

Maternal genetic and environmental factors can influence the growth and development of the fetus. First, the pregnant woman's own MTHFRC677T gene mutation is a risk factor for fetal CHD. The MTHFR gene has two different alleles (C and T), and T is associated with decreased enzyme activity and increased risk of homocysteinemia, resulting in decreased MTHFR activity and elevated plasma HCY. Maternal HCY is a risk factor for CHD, especially in the low-folate state, which increases the risk of CHD. MTHFR has important implications for determining the level of HCY. Studies have shown that high HCY induces and alters apoptosis by stimulating certain signals, thereby inducing cardiac malformation. Animal experiments have shown that hyperhomocysteinemia has a significant toxic effect on embryonic heart development in pregnant mice.

References:

Khorshied, M. M. , Shaheen, I. A. M. , Khalil, R. E. A. , & Sheir, R. E. . (2014). Methylene tetrahydrofolate reductase (mthfr) gene polymorphisms in chronic myeloid leukemia: an egyptian study. Medical Oncology, 31(1), 1-6.
Levin, B. L. , & Varga, E. . (2016). Mthfr: addressing genetic counseling dilemmas using evidence-based literature. Journal of Genetic Counseling, 25(5), 901-911.
Liew, S. C. , & Gupta, E. D. . (2015). Methylenetetrahydrofolate reductase (mthfr) c677t polymorphism: epidemiology, metabolism and the associated diseases. European Journal of Medical Genetics, 58(1), 1-10.

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