Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.5.7.1 (methylenetetrahydrofolate reductase)
2,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The missense mutation in the 677th nucleotide (C677T) of methylenetetrahydrofolate reductase gene causes substitution of valine (V) for alanine (A) resulting in three genotypes VV, VA and AA. The VV genotype causes hyperhomocysteinemia and may be a risk factor for coronary artery disease. We determined genotypes by polymerase chain reaction and subsequent restriction fragment length analysis and compared them in 84 patients with type 2 diabetes and in 115 non-diabetic subjects with and without coronary disease. Fractional urinary excretion rate of albumin was assessed by nephelometry. The VV, VA, and AA frequencies in the diabetic and in the control groups were 0.095, 0.357, 0.548 and 0.061, 0.417, 0.522, respectively (p = NS, diabetic vs. controls, chi2 test). Genotype frequencies did not differ in either diabetic or control subjects between those with or those without coronary disease (chi2 test). The fractional urinary excretion rate of albumin (mean +/-SD) in diabetic patients with the VV genotype i.e. 1.59 +/-0.71 was lower (Kruskall-Wallis test p = 0.002) than in the other genotypes i.e. VA 5.98 +/-9.75 and AA 3.75 +/-4.77, respectively (post-hoc Mann-Whitney test VV vs. VA p = 0.005 and VV vs. AA p = 0.054, respectively). We found that in patients with type 2 diabetes the methylenetetrahydrofolate reductase VV genotype was associated with a low urinary albumin excretion but not with coronary artery disease or diabetes per se.
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PMID:Mutation C677T of methylenetetrahydrofolate reductase gene is not associated with coronary artery disease, but possibly with albuminuria, in type 2 diabetic patients. 980 73

An increased total plasma homocysteine level is an established risk factor for atherosclerotic vascular disease. The plasma level of homocysteine is influenced by both environmental and genetic factors. An important genetic determinant of plasma homocysteine is a common amino acid dimorphism (Ala222Val) in the methylenetetrahydrofolate reductase (MTHFR) gene. Individuals homozygous for the Val allele have significantly higher homocysteine levels than those with an Ala/Val or Ala/Ala genotype. Moreover, the Val/Val genotype has been claimed to be a strong genetic risk factor for atherosclerosis. The aim of the present study is: (1) to determine the risk associated with the MTHFR dimorphism by comparing the genotype distribution in patients with premature atherosclerosis with that in a group of healthy controls; and (2) to investigate the relationship between the MTHFR genotype and parameters of homocysteine metabolism. The patient group consisted of 257 consecutive referred individuals with angiographically proven premature ( <50 years of age) arterial disease (coronary, and/or peripheral vascular disease). A total of 272 healthy hospital workers without a history of vascular disease were selected as a control group. The MTHFR-genotype was determined by PCR and gel-electrophoresis. A methionine-loading test was performed on 245 patients, and, in addition to homocysteine, levels of folate and vitamin B12 were measured. We found a strong correlation between MTHFR genotype and plasma homocysteine levels both before and after methionine loading. In addition, the MTHFR genotype seems important for the inverse relationship between homocysteine and folate and vitamin B12 levels. Lastly, the MTHFR genotype distribution was not different between patient and control groups. MTHFR genotype is a strong determinant of plasma homocysteine levels. Moreover, the plasma level of folate, which by itself influences homocysteine levels, is also dependent on the MTHFR genotype. In Val/Val genotypes, low levels of both folate and B12 lead to a relatively large increase in homocysteine levels. Nevertheless, the MTHFR genotype does not increase the risk for premature coronary artery disease.
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PMID:The effect of a common methylenetetrahydrofolate reductase mutation on levels of homocysteine, folate, vitamin B12 and on the risk of premature atherosclerosis. 986 49

Elevated plasma homocysteine levels are associated with increased risk for cardiovascular disease and neural tube defects in humans. Folate treatment decreases homocysteine levels and dramatically reduces the incidence of neural tube defects. The flavoprotein methylenetetrahydrofolate reductase (MTHFR) is a likely target for these actions of folate. The most common genetic cause of mildly elevated plasma homocysteine in humans is the MTHFR polymorphism A222V (base change C677-->T). The X-ray analysis of E. coli MTHFR, reported here, provides a model for the catalytic domain that is shared by all MTHFRs. This domain is a beta8alpha8 barrel that binds FAD in a novel fashion. Ala 177, corresponding to Ala 222 in human MTHFR, is near the bottom of the barrel and distant from the FAD. The mutation A177V does not affect Km or k(cat) but instead increases the propensity for bacterial MTHFR to lose its essential flavin cofactor. Folate derivatives protect wild-type and mutant E. coli enzymes against flavin loss, and protect human MTHFR and the A222V mutant against thermal inactivation, suggesting a mechanism by which folate treatment reduces homocysteine levels.
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PMID:The structure and properties of methylenetetrahydrofolate reductase from Escherichia coli suggest how folate ameliorates human hyperhomocysteinemia. 1020 87

Folate derivatives are essential for DNA synthesis and methylation. A large proportion of the Caucasian population is heterozygous for a common substitution, 677C-->T (alanine-->valine), in methylenetetrahydrofolate reductase (MTHFR), an enzyme of folate interconversion. Homozygous mutant individuals, approximately 10-15% of North Americans, have been reported to have a reduced risk of colorectal cancer. We examined lymphocyte and tumor tissue DNA from colorectal carcinoma patients from two different populations to assess loss of heterozygosity (LOH) of MTHFR. We observed LOH in approximately 16% of colorectal tumors; in 8 of the 11 tumors with LOH, the mutant valine allele was lost. Additional studies are required to determine if preferential loss of the mutant allele is a common finding that could contribute to colorectal tumorigenesis.
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PMID:Loss of heterozygosity of methylenetetrahydrofolate reductase in colon carcinomas. 1020 98

Neural tube defects (NTDs) are a common birth defect, seen in approximately 1/1,000 births in the United States. NTDs are considered a complex trait where several genes, interacting with environmental factors, create the phenotype. Using a Midwestern NTD population consisting of probands, parents, and siblings from Iowa, Minnesota, and Nebraska, we analyzed a range of candidate genes, including 5,10-methylenetetrahydrofolate reductase (MTHFR), folate receptors-alpha (FOLR1; hereafter abbreviated "FR-alpha") and -beta (FOLR2; hereafter, "FR-beta"), methionine synthase (hereinafter, "MS"), T, the human homolog of the murine Brachyury gene, and the paired-box homeotic gene 3 (PAX3), for association with NTDs. We were unable to demonstrate an association using a previously described Ala-->Val mutation in MTHFR and the majority of our NTD populations. However, we discovered a silent polymorphism in exon 6 of MTHFR which conserved a serine residue and which showed significant association with NTDs in our Iowa population. Analysis of exon 7 of MTHFR then demonstrated an Ala-->Glu mutation which was significantly associated with our Iowa NTD population; however, we could not replicate this result either in a combined Minnesota/ Nebraska or in a California NTD population. Using polymorphic markers for MS, FR-beta, T, and PAX3, we were unable to demonstrate linkage disequilibrium with our NTD populations. A mutation search of FR-alpha revealed one proband with a de novo silent mutation of the stop codon. This work provides a new panel of genetic variants for studies of folate metabolism and supports, in some NTD populations, an association between MTHFR and NTDs.
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PMID:Analysis of select folate pathway genes, PAX3, and human T in a Midwestern neural tube defect population. 1033 59

We retrospectively examined the relationship between the genotype of the angiotensin-converting enzyme (ACE) gene or the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, and the secondary cardiac events after myocardial infarction. The study population consisted of 176 patients (ACE genotype: deletion homozygote (DD)=20, insertion/deletion heterozygote (ID)=91, insertion homozygote (II)=65; MTHFR genotype: valine homozygote (VV)=37, valine/alanine heterozygote (VA)=71, alanine homozygote (AA)=68) with acute or recent myocardial infarction at the start of the follow-up. We defined the occurrence of cardiac death, recurrent myocardial infarction, or admission due to unstable angina as the endpoint. Cardiac events related coronary intervention were excluded from the endpoints. During the follow-up (1903+/-1414 days), four patients had cardiac death, 12 patients had recurrent myocardial infarction and 13 patients had admission due to unstable angina. A Cox analysis revealed that the endpoints were significantly associated with diabetes mellitus (RR=4.423), total cholesterol level (RR=1.025) and the genotype of the ACE gene (RR=4.490). The ID or DD genotype of the ACE gene was associated with higher occurrence of the endopoints. The MTFHR gene was not associated with the endopoint. The present results suggest that the presence of the deletion allele of the ACE gene may be a risk factor for secondary cardiac events after myocardial infarction.
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PMID:D allele of the angiotensin-converting enzyme gene is a risk factor for secondary cardiac events after myocardial infarction. 1045 99

We assessed the contribution of serum homocysteine levels, an independent risk factor for vascular disease, and of the methylenetetrahydrofolate reductase (MTHFR) C677T mutation to the variability of carotid intimal-medial thickness (IMT) in patients with non-insulin-dependent diabetes mellitus (NIDDM). Ninety-five patients (33 males and 62 females, mean age 53 +/- 10 years) without nephropathy or other vascular complications were enrolled. Fasting total serum homocysteine and other biochemical analytes were measured. The MTHFR polymorphism was determined by the polymerase chain reaction. Common carotid IMT and plaques or stenoses in the carotid district were measured by ultrasonography. Serum total homocysteine concentrations were higher in subjects with the mutant (Val/Val) genotype than in those with the Ala/Val plus Ala/Ala genotypes (P = 0.02). On univariate analysis, carotid IMT was significantly associated with age, body mass index (BMI), systolic blood pressure, and total cholesterolemia. No significant association was found between IMT and serum homocysteine or the MTHFR polymorphism, although a slightly greater IMT was observed in the homozygous Val genotypes. On multiple regression analysis, only age and BMI were independently associated with IMT and explained about 40% of IMT variability. The results did not change when the analysis was restricted to the subgroups with or without atherosclerotic plaques in the carotid district. In 95 Italian NIDDM patients without nephropathy, neither basal levels of serum total homocysteine nor the MTHFR C677T polymorphism predicted significant changes in common carotid intimal-medial thickness.
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PMID:Serum homocysteine, MTHFR gene polymorphism, and carotid intimal-medial thickness in NIDDM subjects. 1050 Mar 10

We report white monozygotic twins with moyamoya disease (MMD) (adult ischemic type). Both had cerebral angiography, MRI, magnetic resonance angiography, SPECT, EEG, human leukocyte antigen (HLA) typing, evaluation of thrombophilia, and immunologic and karyotype analysis. The clinical features and HLA phenotypes described in Asian monozygotic twins with MMD were not found in our patients. However, genetic analysis revealed a homozygous state for C-->T (Ala-->Val substitution) in position 677 of the methylenetetrahydrofolate reductase-encoding gene.
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PMID:Moyamoya disease in Italian monozygotic twins. 1052 94

Inherited gene defects related to the coagulation system have been reported as risk factors for ischemic stroke. These gene defects include a G-A transition at nucleotide 1691 in exon 10 of the Factor V gene causing activated protein C resistance; a G-A transition in the 3' untranslated region of the prothrombin gene at nucleotide position 20210 (G-A), which is associated with increased levels of prothrombin activity; and a C-T polymorphism at nucleotide 677 in the methylenetetrahydrofolate reductase gene responsible for an alanine to valine substitution, resulting in the synthesis of a thermolabile form of methylenetetrahydrofolate reductase that causes increased levels of homocysteine. The case-control study included 28 patients with cerebral infarction; all were 18 years of age or younger (range, 10 months to 18 years). Seven (25%) of the 28 patients were heterozygous for the FV1691 mutation. Five (17.8%) of the patients carried the PT20210A mutation. Two (7.1%) of the patients carried both mutations. When compared to controls, the difference was significant for both mutations (P = .007; .04). The frequency of allele T of methylenetetrahydrofolate reductase 677 was 0.3214, which was not significant when compared to controls (0.231; P = .3). A total of 12 (42.8%) patients carried one or both of the mutations FV1691 G-A and PT20210 G-A. From our data, it appears that FV1691 G-A and PT20210 G-A are associated with cerebral infarct risk independently. Risk assessment of double prothrombotic gene alterations did not reveal synergy between these mutations. In conclusion, the presence of FV1691 A and PT20210 A mutations but not the methylenetetrahydrofolate reductase 677 TT mutation correlate with the occurrence of cerebral infarction in children.
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PMID:Factor V1691 G-A, prothrombin 20210 G-A, and methylenetetrahydrofolate reductase 677 C-T variants in Turkish children with cerebral infarct. 1059 55

The alanine/valine (A/V) gene polymorphism of 5, 10-methylenetetrahydrofolate reductase (MTHFR), one of the key enzymes catalyzing remethylation of homocysteine, has been reported and the VV genotype is associated with increased plasma homocysteine levels as a result of the reduced activity and increased thermolability of this enzyme. Although previous studies have suggested that the VV genotype is a risk factor for arterial occlusive disease, whether the VV genotype is a risk factor for venous thrombosis is still controversial. Here we screened 72 Japanese patients with deep venous thrombosis (DVT) and 85 controls for this mutation, and we measured plasma levels of homocysteine to determine whether the thermolabile variant with the VV genotype is a risk factor for DVT in a Japanese population. Of the 72 patients with DVT, 10 (13.9%) were found to be homozygous for the VV genotype, and in 6 (7.0%) of 85, control individuals and the difference was not significant (odds ratio=2.12, 95% CI=0.73-6.16, p=0.19). When we divided the DVT patients into subgroups, with and without predisposition of thrombophilia, including deficiencies of proteins C and S, plasminogen, and lupus anticoagulant, the prevalence of the VV genotype in DVT patients with predisposition was significantly higher than that of the normal controls (odds ratio=5.99, 95% CI=1. 56-22.96, p=0.01). However, the prevalence of the VV genotype in DVT patients without predisposition was not significantly different from that of the normal controls (odds ratio=1.20, 95% CI=0.32-4.47, p=0. 75). The plasma homocysteine levels in patients with DVT (11.6+/-5.2 nmol/ml) was not significantly different from that of the control subjects (11.6+/-3.7 nmol/ml). Individuals with the VV genotype showed higher plasma homocysteine levels (15.4+/-6.9 nmol/ml) than did individuals with the AV genotype (11.2+/-3.7 nmol/ml, p=0.009) or in individuals with the AA genotype (11.1+/-4.2 nmol/ml, p=0.004). Serum folate and vitamin B12 levels were not correlated with the plasma homocysteine levels. In conclusion, even though homozygosity for the VV genotype of the MTHFR gene was associated with higher plasma homocysteine levels, we found no association between plasma levels of homocysteine and DVT or between the genotype of the MTHFR gene and the DVT incidence. However, we found that the VV genotype of the MTHFR gene is a risk factor for DVT only when combined with the predisposition of thrombophilia.
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PMID:Common C677T polymorphism in the methylenetetrahydrofolate reductase gene increases the risk for deep vein thrombosis in patients with predisposition of thrombophilia. 1070 28


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