Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification

Abstract

Methylenetetrahydrofolate reductase (MTHFR) catalyses the reduction of methylenetetrahydrofolate to methyltetrahydrofolate, a cofactor for homocysteine methylation to methionine. MTHFR deficiency, an autosomal recessive disorder, results in homocysteinemia. Using degenerate oligonucleotides based on porcine peptide sequence data, we isolated a 90-bp cDNA by PCR from pig liver RNA. This cDNA was used to isolate a human cDNA, the predicted amino acid sequence of which shows strong homology to porcine MTHFR and to bacterial metF genes. The human gene has been localized to chromosome 1p36.3. Two mutations were identified in MTHFR-deficient patients: a missense mutation (Arg to Gln), in a residue conserved in bacterial enzymes, and a nonsense mutation (Arg to Ter).

Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and the risk of primary Hepatocellular Carcinoma (HCC) in a Chinese population

“…As a precursor of S-adenosylmethionine (SAM), methionine is the universal methyl donor for DNA methylation [2,3,34]. Individuals carrying the variant MTHFR 677TT genotype or 677CT have about 30% or 65% of enzyme activity, respectively, in vitro as compared with the CC wild type [2].…”

“…A C-to-T transition at nucleotide 677 (C677T) in exon four results in an alanine to valine exchange and affects the catalytic domain of the enzyme, which leads to reduced enzyme activity. The enzyme activity levels are approximately 70% lower than the common form, and individuals who are homozygous and heterozygous for this polymorphism have an increased amount of homocysteine [2,3]. Another common variant of the MTHFR gene is an A-to-C transversion at position 1298 (A1298C) in exon seven, which causes a glutamine to alanine exchange at position 429; this polymorphism influences specific activity of the enzyme to a lesser extent than the MTHFR C677T polymorphism [4].…”

The effects of polymorphisms in methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) on the risk of cervical intraepithelial neoplasia and cervical cancer in Korean women

“…Polymorphisms in the genes for MTHFR C677T (rs1801133) and A1298C (rs1801131), MTR A2756G (rs1805087), and MTRR A66G (rs1801394) are known to have functional relevance [4]. Genetic variants of these genes alter their respective enzyme activities [4,[8][9][10][11], with consequent abnormalities in DNA methylation and synthesis, and therefore influence susceptibility to cancer [4]. Most studies of cervical cancer have focused on two putative functional polymorphisms in MTHFR C677T and A1298C; however, the findings are inconsistent [12][13][14][15][16][17][18].…”

Identification of differential transcript profiles between mutual crossbred embryos of zebrafish (Danio rerio) and Chinese rare minnow (Gobiocypris rarus) by cDNA-AFLP

“…Acid alpha glucosidase (ZR9) is an active enzyme in lysosomes that breaks down glycogen into glucose, to provide an important energy source for cells [31]. Methylenetetrahydrofolate reductase (Mthfr) (RZ3) is a crucial enzyme that regulates the metabolism of homocysteine and methionine by catalyzing the reduction of methylenetetrahydrofolate to methyltetrahydrofolate, the methyl donor for methionine synthesis from homocysteine [32]. Glycylpeptide N-tetradecanoyltransferase 2 (RZ6), which belongs to the N-myristoyltransferase (NMT) family, catalyzes the reaction of N-terminal myristoylation of many proteins that have diverse biological functions such as signal transduction, cellular transformation, and oncogenesis [33].…”