The enzyme is coded by the
gene with the symbol
MTHFR on
chromosome 1 location p36.3 in humans. There are DNA sequence variants (
genetic polymorphisms) associated with this gene. In 2000 a report brought the number of polymorphisms up to 24. Two of the most investigated are C677T (
rs1801133) and A1298C (
rs1801131)
single nucleotide polymorphisms (SNPs). While multiple published studies have drawn relationships between these SNPs and a wide variety of diseases, the American College of Medical Genetics has issued an official Practice Guideline recommending against testing or reporting on these two variants, citing "Recent meta-analyses have disproven an association between hyperhomocysteinemia and risk for coronary heart disease and between MTHFR polymorphism status and risk for venous thromboembolism. There is growing evidence that MTHFR polymorphism testing has minimal clinical utility.". However, a more recent study has shown that the presence of the C677T and/or A1298C polymorphisms may have a critical impact on leukemic cell response to MYC-targeting therapies. This study demonstrates that MTHFR deficiency indeed increases leukemic cell resistance to a variety of MYC-targeting pharmacological agents, including BET protein small-molecule inhibitors.
C677T SNP (Ala222Val) The MTHFR
nucleotide at position 677 in the gene has two possibilities: C (
cytosine) or T (
thymine). C at position 677 (leading to an alanine at amino acid 222) is the reference
allele. The 677T allele (leading to a valine substitution at amino acid 222) encodes a
thermolabile alternative enzyme variant with reduced activity. Both reference and alternative genotypes are common, with the alternative allele frequency at 10-35%, depending on ancestry. Individuals with two copies of 677C (677CC) have the most common genotype. 677TT individuals (homozygous) have lower MTHFR activity than CC or CT (heterozygous) individuals. About ten percent of the
North American population are T-
homozygous for this polymorphism. There is ethnic variability in the frequency of the T allele – frequency in Mediterranean/Hispanics is greater than the frequency in Caucasians which, in turn, is greater than in Africans/African-Americans. The degree of enzyme thermolability (assessed as residual activity after heat inactivation) is much greater in 677TT individuals (18–22%) compared with 677CT (56%) and 677CC (66–67%). Individuals of 677TT are predisposed to mild
hyperhomocysteinemia (high blood homocysteine levels), because they have less active MTHFR available to produce 5-methyltetrahydrofolate (which is used to decrease homocysteine). Low dietary intake of the vitamin
folate can also cause mild hyperhomocysteinemia. Low folate intake affects individuals with the 677TT genotype to a greater extent than those with the 677CC/CT genotypes. 677TT (but not 677CC/CT) individuals with lower
plasma folate levels are at risk for elevated plasma homocysteine levels. In studies of human recombinant MTHFR, the protein encoded by 677T loses its FAD cofactor three times faster than the wild-type protein. 5-Methyl-THF slows the rate of FAD release in both the wild-type and mutant enzymes, although it is to a much greater extent in the mutant enzyme. arterial and venous
thrombosis, and
cardiovascular disease. 677TT individuals are at an increased risk for
acute lymphoblastic leukemia and
colon cancer. Mutations in the
MTHFR gene could be one of the factors leading to increased risk of developing
schizophrenia. Schizophrenic patients having the risk allele (T\T) show more deficiencies in
executive function tasks. The C677T genotype used to be associated with increased risk of
recurrent pregnancy loss (RPL) in non Caucasians, however this link has been disproved in recent years. The American College of Medical Genetics recommendation guidelines currently state that people with recurrent pregnancy loss should not be tested for variants in the MTHFR gene. There is also a tentative link between MTHFR mutations and
dementia. One study of an elderly Japanese population found correlations between the MTHFR 677CT mutation, an
Apo E polymorphism, and certain types of senile dementia. Other research has found that individuals with folate-related mutations can still have a functional deficiency even when blood levels of
folate are within the normal range, and recommended supplementation of
methyltetrahydrofolate to potentially prevent and treat dementia (along with depression). A 2011 study from China also found that the C677T SNP was associated with
Alzheimer's disease in Asian populations (though not in Caucasians). C677T polymorphism is associated with risk of
myocardial infarction in African, North American, and elderly populations. The
CDC provides a web page with information on the
A1298C SNP (Glu429Ala) At nucleotide 1298 of the MTHFR, there are two possibilities: A or C. 1298A (leading to a Glu at amino acid 429) is the most common while 1298C (leading to an Ala substitution at amino acid 429) is less common. 1298AA is the "normal" homozygous, 1298AC the heterozygous, and 1298CC the homozygous for the "variant". In studies of human recombinant MTHFR, the protein encoded by 1298C cannot be distinguished from 1298A in terms of activity, thermolability, FAD release, or the protective effect of 5-methyl-THF. MTHFR A1298C may play a role as either a driver in the development of
major depressive disorder or as a predictive or diagnostic marker, possibly in combination with C677T.
Detection of MTHFR polymorphisms A triplex tetra-primer ARMS-PCR method was developed for the simultaneous detection of C677T and A1298C polymorphisms with the A66G MTRR polymorphism in a single PCR reaction.
Severe MTHFR deficiency Severe
MTHFR deficiency is rare (about 50 cases worldwide) and caused by mutations resulting in 0–20% residual enzyme activity. A study on the Chinese
Uyghur population indicated that rs1801131
polymorphism in MTHFR was associated with nsCL/P in Chinese Uyghur population. Given the unique genetic and environmental characters of the Uyghur population, these findings may be helpful for exploring the pathogenesis of this complex disease. ==Epigenetics==