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)

A diagnosis of methylenetetrahydrofolate reductase (MTHFR) deficiency was made in four sibs at different ages. The first three, including a pair of twins, had retarded psychomotor development, poor social contact, and seizures. Biologically, hyperhomocysteinemia and hypomethioninemia were found associated with low folate levels in serum and red cells, especially undetectable methyltetrahydrofolate in red cells. In the fourth child, prenatal diagnosis was not conclusive because of moderate decrease of enzymatic activity in chorionic villi and trophoblast. The girl was also affected, as shown by hyperhomocysteinemia and low folate levels found several days after birth. A 677C-->T (Ala-->Val) mutation was found in a homozygous state in the four children and in the father. Additionally, a second homozygous mutation, 1081C-->T, changing an arginine to cysteine also was identified in all of the children, whereas the distantly consanguineous parents were heterozygous. This amino acid substitution affecting an arginine residue in a sequence located at the end of catalytic domain seems critical for the function of the enzyme. The difficulty of prenatal diagnosis is discussed given the variability found in enzymatic activity and in the clinical phenotypes.
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PMID:Methylenetetrahydrofolate reductase deficiency in four siblings: a clinical, biochemical, and molecular study of the family. 1076

Homocysteine is a sulphur-containing amino acid that is derived primarily from protein of animal origin. Classical homocystinuria is an inherited metabolic disorder that arises from defects in either the re-methylation or trans-sulphuration pathways of homocysteine metabolism and leads to skeletal abnormalities, mental retardation and a high risk of vascular disease. In contrast, moderate hyperhomocysteinaemia is associated with an increased risk of both arterial and venous thrombotic disease but no other abnormalities. This increased risk appears to be independent of other conventional risk factors. Many cases of hyperhomocysteineaemia have been attributed to defects in the enzyme cystathionine-beta-synthase (CBS) but this accounts for less than 1.5% of cases. A thermolabile variant of the enzyme methylenetetrahydrofolate reductase (MTHFR) arises from a C --> T transition at nucleotide 677 in the MTHFR gene resulting in an alanine-to-valine substitution. While the mutation does not appear to be associated with an increased risk of vascular disease, it results in excessively high homocysteine levels in response to a low or low-normal serum folate. Supplementation of the diet with folate, B6 and B12 can reduce homocysteine levels and this is the mainstay of treatment. Supplementation of grain with folate is undertaken in the USA to reduce the risk of neural tube defects in pregnant women. However, by reducing plasma homocysteine levels, it is estimated that this will save up to 50,000 lives per annum.
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PMID:Hyperhomocysteinaemia. 1085 81

An association between preeclampsia (PE) and a common missense mutation of the methylenetetrahydrofolate reductase gene (MTHFR), a C to T substitution at nucleotide 677 (C677T), which converts an alanine to a valine residue, has been reported in Italian and Japanese populations. We examined 101 cases of hypertension in pregnancy (HP), including 73 cases of PE, and 215 normal pregnancy controls to confirm the association in Japanese women. No significant differences of the frequency of the T677 allele frequency or percentage of T677 homozygotes were detected among the various types of cases: HP (0.38, 12%, respectively), severe HP (0. 40, 12%), PE (0.38, 11%), severe PE (0.41, 11%), primiparous HP (0. 40, 12%), primiparous PE (0.44, 18%), nonelderly HP (0.39, 13%), nonelderly PE (0.40, 14%), nonobese HP (0.38, 12%), nonobese PE (0. 39, 10%), HP without homozygous T235 of the angiotensinogen gene (TT of AGT) (0.38, 15%), PE without TT of AGT (0.38, 15%), and controls (0.38, 15%). The results indicate that T677 of MTHFR may not be a risk factor for PE in Japanese population.
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PMID:Absence of association between a common mutation in the methylenetetrahydrofolate reductase gene and preeclampsia in Japanese women. 1086 14

The missense mutation, C677T (Ala--->Val), in the methylenetetrahydrofolate reductase (MTHFR) gene, is related to hyperhomocysteinemia and is regarded as a risk factor for coronary artery disease and neural tube defects. The prevalence of this mutation was reported to differ among various ethnic groups, but there are few reports concerning Asian populations. We have investigated the frequencies of C677T mutation in 124 Korean infants (residents in Seoul city, Korea) and 115 Japanese adults (residents in Kobe city, Japan), and compared them with the reported data from other ethnic groups. The frequencies of the three genotypes in Koreans were as follows: C/C (wild homozygosity) 0.27, C/T (heterozygosity) 0.66, T/T (mutated homozygosity) 0.07, while those in Japanese were as follows: C/C 0.44, C/T 0.40, T/T 0.16. There was a marked difference in the genotype frequencies between the two populations (chi-square = 16.67, P = 0.0002), even though they are closely related in genetic background. The high C/T genotype frequency led to significant deviation from Hardy-Weinberg equilibrium (chi-square = 17.35, P = 0.00003). Deviation from Hardy-Weinberg equilibrium has not been found in any other ethnic groups. The high frequency of C/T genotype may offer Koreans a selective advantage.
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PMID:C677T mutation of the methylenetetrahydrofolate reductase gene among the Korean infants in Seoul city. 1098 60

With the identification of hyperhomocysteinemia as a risk factor for cardiovascular disease, an understanding of the genetic determinants of plasma homocysteine is important for prevention and treatment. It has been known for some time that homocystinuria, a rare inborn error of metabolism, can be due to genetic mutations that severely disrupt homocysteine metabolism. A more recent development is the finding that milder, but more common, genetic mutations in the same enzymes might also contribute to an elevation in plasma homocysteine. The best example of this concept is a missense mutation (alanine to valine) at base pair (bp) 677 of methylenetetrahydrofolate reductase (MTHFR), the enzyme that provides the folate derivative for conversion of homocysteine to methionine. This mutation results in mild hyperhomocysteinemia, primarily when folate levels are low, providing a rationale (folate supplementation) for overcoming the genetic deficiency. Additional genetic variants in MTHFR and in other enzymes of homocysteine metabolism are being identified as the cDNAs/genes become isolated. These variants include a glutamate to alanine mutation (bp 1298) in MTHFR, an aspartate to glycine mutation (bp 2756) in methionine synthase, and an isoleucine to methionine mutation (bp 66) in methionine synthase reductase. These variants have been identified relatively recently; therefore additional investigations are required to determine their clinical significance with respect to mild hyperhomocysteinemia and vascular disease.
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PMID:Genetic modulation of homocysteinemia. 1101 43

Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by primary hypercholesterolemia and premature coronary artery disease (CAD). However, the development of CAD in FH shows considerable interindividual variations. Elevated levels of plasma homocysteine have been recognized as independent risk factors for CAD. A 5,10-methylenetetrahydrofolate reductase (MTHFR) gene mutation (valine [V] was substituted for alanine [A]) has been reported to be associated with elevated levels of plasma homocysteine in mutant homozygotes (i.e., VV). We studied 199 consecutive male heterozygous FH patients, 99 with and 100 without CAD. In the CAD group, genotype VV and V alleles were significantly more frequent than in the non-CAD group (15% vs 7% in genotypes [p = 0.035] and 0.41 vs 0.30 in alleles [p = 0.017]). The mean ages at onset in the CAD group were 50, 51, and 43 years for genotypes AA, AV, and VV, respectively (p <0.05); the age of onset of CAD in genotype VV was significantly lower than in the other 2 genotypes. Kaplan-Meier survivor curves indicated that the development of CAD was significantly accelerated by MTHFR mutation, probably in a gene dose-dependent manner. Furthermore, only MTHFR genotype VV was shown to be an independent predictor of the early onset of CAD in a stepwise multiple regression analysis. The mean plasma homocysteine levels of genotype VV were significantly higher than those of the other 2 genotypes. Thus, the MTHFR mutation appears to accelerate the onset of CAD through elevation of plasma homocysteine levels in male heterozygous patients with FH.
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PMID:Effect of common methylenetetrahydrofolate reductase gene mutation on coronary artery disease in familial hypercholesterolemia. 1102 98

Maternal folic acid supplementation in early pregnancy has been suggested to play a role in the prevention of nonsyndromic orofacial cleft, i.e., cleft lip with or without cleft palate (CL/P). Moreover, some authors demonstrated association of the C-->T mutation (C677T), converting an alanine to a valine residue in 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, with other congenital anomalies such as neural tube defects (NTDs). Because of MTHFR's involvement in the metabolism of folate, we investigated 64 CL/P patients and their parents for C677T MTHFR mutation. No linkage disequilibrium was found using the transmission disequilibrium test (TDT). However, a significantly higher mutation frequency was detected in mothers of CL/P patients compared to controls. The odds ratios calculated for mothers having CT or TT genotype, compared to the normal CC genotype, were 2.75 (95% confidence interval 1.30-5.57) and 2.51 (1.00-6.14), respectively. These results support the involvement of the folate pathway in the etiology of CL/P, and indicate an effect of the maternal genotype, rather than influence of the embryo's genotype.
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PMID:C677T variant form at the MTHFR gene and CL/P: a risk factor for mothers? 1117 82

A common mutation in methylenetetrahydrofolate reductase (MTHFR), 677C-->T, is associated with reduced enzyme activity, a thermolabile enzyme and mild hyperhomocysteinemia, a risk factor for vascular disease. Recently, a second common mutation (1298A-->C; glutamate to alanine) was reported, but this mutation was suggested to increase homocysteine only in individuals who carried the bp677 variant. To evaluate the functional consequences of this mutation, we performed site-directed mutagenesis and in vitro expression. For in vivo assessment of clinical impact, we examined the 1298A-->C genotypes and plasma homocysteine in 198 individuals from the NHLBI Family Heart Study that had previously been assessed for the 677 substitution. Site-directed mutagenesis of the human cDNA was performed to generate enzymes containing each of the two mutations, as well as an enzyme containing both substitutions. Enzyme activity and thermolability were assessed in bacterial extracts. The activity of the wild-type cDNA was designated as 100%; mutant enzymes containing the 1298 and 677 mutations separately had 68% (+/-5.0) and 45% (+/-10.8), respectively, of control activity while the enzyme containing both mutations had 41% (+/-12.8) of control activity. The 1298 mutation was not associated with a thermolabile enzyme. In the Family Heart Study, fasting homocysteine was significantly higher (P<0.05) in individuals heterozygous for both substitutions, compared to individuals who carried only the 677C-->T variant. This study suggests that two variants in MTHFR should be assessed as genetic risk factors for hyperhomocysteinemia.
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PMID:The 1298A-->C polymorphism in methylenetetrahydrofolate reductase (MTHFR): in vitro expression and association with homocysteine. 1139 38

The C677T mutation in 5,10-methylenetetrahydrofolate reductase (MTHFR) predicts substitution of valine for alanine at residue 223 (A223V). This thermolabile form of MTHFR has 50% reduced activity, has been associated with hyperhomocystinemia, and is a described risk factor for thrombosis in adults.(1-3) In addition, it has been associated with birth defects in the infants of affected mothers and with recurrent fetal losses.(4-6) We report the occurrence of sinovenous thrombosis in a newborn infant who presented with seizures. Both infant and mother were subsequently identified as having homozygous C677T alleles for MTHFR.
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PMID:Neonatal sinovenous thrombosis associated with homozygous thermolabile methylenetetrahydrofolate reductase in both mother and infant. 1189 28

Folic acid supplementation can reduce the incidence of neural tube defects. The first reported genetic risk factor for neural tube defects is a C677T mutation in the 5,10-methylenetetrahydrofolate reductase gene, resulting in decreased activity of the enzyme. We examined the enzyme mutation role of methylenetetrahydrofolate reductase in the etiology of neural tube defects in our population. The study group consisted of 204 Puerto Rican individuals including 37 pregnant females with a prenatal diagnosis of neural tube defects in their fetuses, 31 newborns, 36 fathers, and 100 healthy adults. The prevalence of the C677T mutation was examined. Homozygosity for the alanine to valine substitution (TT) was observed in 9% of the controls and 19% of the mothers with children with neural tube defects. Our results indicate that the presence of the T allele at the methylenetetrahydrofolate reductase 677 position may increase the risk of giving birth to an infant with a neural tube defect.
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PMID:Presence of the 5,10-methylenetetrahydrofolate reductase C677T mutation in Puerto Rican patients with neural tube defects. 1191 66


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