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1

Severe and mild mutations in cis for the methylenetetrahydrofolate reductase (MTHFR) gene, and description of five novel mutations in MTHFR.  

PubMed Central

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate, a methyl donor in the conversion of homocysteine to methionine. Patients with severe MTHFR deficiency have hyperhomocysteinemia, hypomethioninemia, and a range of neurological and vascular findings with a variable age at onset. We have previously described nine mutations in patients with severe MTHFR deficiency. A mild form of MTHFR deficiency, associated with a thermolabile enzyme, has been proposed as a genetic risk factor for cardiovascular disease and for neural tube defects. We have shown that a common missense mutation (an alanine-to-valine substitution) encodes this thermolabile variant. We now report an additional five mutations causing severe MTHFR deficiency and an analysis of genotype (alanine/valine status) and enzyme thermolability in 22 patients with this inborn error of metabolism. Six of these patients have four mutations in the MTHFR gene-two rare mutations causing severe deficiency and two mutations for the common alanine-to-valine mutation that results in thermolability. Even in severe MTHFR deficiency, the thermolabile variant is frequently observed, and there is a strong relationship between the presence of this variant and increased enzyme thermolability. Images Figure 1 Figure 2

Goyette, P.; Christensen, B.; Rosenblatt, D. S.; Rozen, R.

1996-01-01

2

Severe and mild mutations in cis for the methylenetetrahydrofolate reductase (MTHFR) gene, and description of five novel mutations in MTHFR.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate, a methyl donor in the conversion of homocysteine to methionine. Patients with severe MTHFR deficiency have hyperhomocysteinemia, hypomethioninemia, and a range of neurological and vascular findings with a variable age at onset. We have previously described nine mutations in patients with severe MTHFR deficiency. A mild form of MTHFR deficiency, associated with a thermolabile enzyme, has been proposed as a genetic risk factor for cardiovascular disease and for neural tube defects. We have shown that a common missense mutation (an alanine-to-valine substitution) encodes this thermolabile variant. We now report an additional five mutations causing severe MTHFR deficiency and an analysis of genotype (alanine/valine status) and enzyme thermolability in 22 patients with this inborn error of metabolism. Six of these patients have four mutations in the MTHFR gene-two rare mutations causing severe deficiency and two mutations for the common alanine-to-valine mutation that results in thermolability. Even in severe MTHFR deficiency, the thermolabile variant is frequently observed, and there is a strong relationship between the presence of this variant and increased enzyme thermolability. PMID:8940272

Goyette, P; Christensen, B; Rosenblatt, D S; Rozen, R

1996-12-01

3

Mortality risk in men is associated with a common mutation in the methylenetetrahydrofolate reductase gene (MTHFR)  

Microsoft Academic Search

An elevated level of homocysteine in plasma is associated with the occurrence of cardiovascular disease. A common ala-to-val mutation in the methylenetetrahydrofolate reductase gene (MTHFR) is associated with an elevated level of plasma homocysteine. We studied the possible detrimental effects of the MTHFR mutation on mortality. Within a population-based study in the city of Leiden, the Netherlands, we first compared

Bastiaan T Heijmans; Jacobijn Gussekloo; Cornelis Kluft; Simone Droog; A Margot Lagaay; Dick L Knook; Rudi GJ Westendorp; Eline P Slagboom

1999-01-01

4

Life-threatening methylenetetrahydrofolate reductase (MTHFR) deficiency with extremely early onset: Characterization of two novel mutations in compound heterozygous patients  

Microsoft Academic Search

Methylenetetrahydrofolate reductase (MTHFR) is a key enzymatic component of the folate cycle, converting 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate, the methyl donor for remethylation of homocysteine into methionine. Severe MTHFR deficiency is a rare recessive disease leading to major hyperhomocysteinemia, homocystinuria, and progressive neurological distress within the two first decades of life. More than 50 mutations have been reported so far in affected

Thierry Forges; Céline Chery; Sandra Audonnet; François Feillet; Jean-Louis Gueant

2010-01-01

5

Characterization of six novel mutations in the methylenetetrahydrofolate reductase (MTHFR) gene in patients with homocystinuria.  

PubMed

Severe deficiency of methylenetetrahydrofolate reductase (MTHFR) is the most common inborn error of folate metabolism. Patients are characterized by severe hyperhomocysteinemia, homocystinuria and a variety of neurological and vascular problems. Eighteen rare mutations have been reported in this group of patients. Two polymorphisms which cause mild enzyme deficiencies have been described (677C-->T and 1298A-->C). The first sequence change encodes a thermolabile enzyme and is associated with mild hyperhomocysteinemia. Six novel point mutations are described in patients with severe deficiency of MTHFR, along with their associated polymorphisms and clinical phenotypes. Of the two nonsense mutations (1762A-->T, 1134C-->G) and four missense mutations (1727C-->T, 1172G-->A, 1768G-->A, and 358G-->A), one was identified in the N-terminal catalytic domain, while the others were located in the regulatory C-terminal region. All four residues affected by missense mutations are conserved in one or more MTHFRs of other species. This report brings the total to 24 mutations identified in severe MTHFR deficiency, with two mutations identified in each of 22 patients. PMID:10679944

Sibani, S; Christensen, B; O'Ferrall, E; Saadi, I; Hiou-Tim, F; Rosenblatt, D S; Rozen, R

2000-01-01

6

Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR)  

Microsoft Academic Search

.   Methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate,\\u000a a co-substrate for homocysteine remethylation to methionine. A human cDNA for MTHFR, 2.2 kb in length, has been expressed\\u000a and shown to result in a catalytically active enzyme of approximately 70 kDa. Fifteen mutations have been identified in the\\u000a MTHFR gene: 14 rare mutations associated with severe enzymatic deficiency

Philippe Goyette; Aditya Pai; Renate Milos; Phyllis Frosst; Pamela Tran; Zhoutao Chen; Manuel Chan; Rima Rozen

1998-01-01

7

Valproic acid increases expression of methylenetetrahydrofolate reductase (MTHFR) and induces lower teratogenicity in MTHFR deficiency  

PubMed Central

Valproate (VPA) treatment in pregnancy leads to congenital anomalies, possibly by disrupting folate or homocysteine metabolism. Since methylenetetrahydrofolate reductase (MTHFR) is a key enzyme of folate interconversion and homocysteine metabolism, we addressed the possibility that VPA might have different teratogenicity in Mthfr+/+ and Mthfr+/? mice and that VPA might interfere with folate metabolism through MTHFR modulation. Mthfr+/+ and Mthfr+/? pregnant mice were injected with VPA on gestational day 8.5; resorption rates and occurrence of neural tube defects (NTDs) were examined on gestational day 14.5. We also examined the effects of VPA on MTHFR expression in HepG2 cells and on MTHFR activity and homocysteine levels in mice. Mthfr+/+ mice had increased resorption rates (36%) after VPA treatment, compared to saline treatment (10%), whereas resorption rates were similar in Mthfr+/? mice with the 2 treatments (25–27%). NTDs were only observed in one group (VPA-treated Mthfr +/+). In HepG2 cells, VPA increased MTHFR promoter activity and MTHFR mRNA and protein (2.5- and 3.7-fold, respectively). Consistent with cellular MTHFR up-regulation by VPA, brain MTHFR enzyme activity was increased and plasma homocysteine was decreased in VPA-treated pregnant mice compared to saline-treated animals. These results underscore the importance of folate interconversion in VPA-induced teratogenicity, since VPA increases MTHFR expression and has lower teratogenic potential in MTHFR deficiency.

Roy, Marc; Leclerc, Daniel; Wu, Qing; Gupta, Sapna; Kruger, Warren D.; Rozen, Rima

2008-01-01

8

Valproic acid increases expression of methylenetetrahydrofolate reductase (MTHFR) and induces lower teratogenicity in MTHFR deficiency.  

PubMed

Valproate (VPA) treatment in pregnancy leads to congenital anomalies, possibly by disrupting folate or homocysteine metabolism. Since methylenetetrahydrofolate reductase (MTHFR) is a key enzyme of folate interconversion and homocysteine metabolism, we addressed the possibility that VPA might have different teratogenicity in Mthfr(+/+) and Mthfr(+/-) mice and that VPA might interfere with folate metabolism through MTHFR modulation. Mthfr(+/+) and Mthfr(+/-) pregnant mice were injected with VPA on gestational day 8.5; resorption rates and occurrence of neural tube defects (NTDs) were examined on gestational day 14.5. We also examined the effects of VPA on MTHFR expression in HepG2 cells and on MTHFR activity and homocysteine levels in mice. Mthfr(+/+) mice had increased resorption rates (36%) after VPA treatment, compared to saline treatment (10%), whereas resorption rates were similar in Mthfr(+/-) mice with the two treatments (25-27%). NTDs were only observed in one group (VPA-treated Mthfr(+/+)). In HepG2 cells, VPA increased MTHFR promoter activity and MTHFR mRNA and protein (2.5- and 3.7-fold, respectively). Consistent with cellular MTHFR upregulation by VPA, brain MTHFR enzyme activity was increased and plasma homocysteine was decreased in VPA-treated pregnant mice compared to saline-treated animals. These results underscore the importance of folate interconversion in VPA-induced teratogenicity, since VPA increases MTHFR expression and has lower teratogenic potential in MTHFR deficiency. PMID:18615588

Roy, Marc; Leclerc, Daniel; Wu, Qing; Gupta, Sapna; Kruger, Warren D; Rozen, Rima

2008-10-01

9

Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR)  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. A human cDNA for MTHFR, 2.2 kb in length, has been expressed and shown to result in a catalytically active enzyme of approximately 70 kDa. Fifteen mutations have been identified in the MTHFR gene: 14 rare mutations associated with severe enzymatic deficiency and 1 common variant associated with a milder deficiency. The common polymorphism has been implicated in three multifactorial diseases: occlusive vascular disease, neural tube defects, and colon cancer. The human gene has been mapped to chromosomal region 1p36.3 while the mouse gene has been localized to distal Chromosome (Chr) 4. Here we report the isolation and characterization of the human and mouse genes for MTHFR. A human genomic clone (17 kb) was found to contain the entire cDNA sequence of 2.2 kb; there were 11 exons ranging in size from 102 bp to 432 bp. Intron sizes ranged from 250 bp to 1.5 kb with one exception of 4.2 kb. The mouse genomic clones (19 kb) start 7 kb 5' exon 1 and extend to the end of the coding sequence. The mouse amino acid sequence is approximately 90% identical to the corresponding human sequence. The exon sizes, locations of intronic boundaries, and intron sizes are also quite similar between the two species. The availability of human genomic clones has been useful in designing primers for exon amplification and mutation detection. The mouse genomic clones will be helpful in designing constructs for gene targeting and generation of mouse models for MTHFR deficiency. PMID:9680386

Goyette, P; Pai, A; Milos, R; Frosst, P; Tran, P; Chen, Z; Chan, M; Rozen, R

1998-08-01

10

Mutations of the MTHFR gene (428C>T and [458G>T+459C>T]) markedly decrease MTHFR enzyme activity  

Microsoft Academic Search

Methylenetetrahydrofolate reductase (MTHFR) is the only route for the synthesis of 5-methyltetrahydrofolate, which is utilized to convert homocysteine to methionine. In this study, we measured the enzyme activity of a mutant MTHFR that was detected in a patient with hyperhomocysteinemia. The 428C>T mutation in exon 2 of the MTHFR gene is a novel mutation, while the [458G>T+459C>T] mutation in exon

Hidetaka Yano; Kazuhiro Nakaso; Kenichi Yasui; Yosuke Wakutani; Hiroyuki Nakayasu; Hisanori Kowa; Yoshiki Adachi; Kenji Nakashima

2004-01-01

11

Combined heterozygosity for methylenetetrahydrofolate reductase (MTHFR) mutations C677T and A1298C is associated with abruptio placentae but not with intrauterine growth restriction  

Microsoft Academic Search

Objective: This study was undertaken to investigate the involvement of MTHFR gene mutations C677T and A1298C implicated in vascular disease, in patients with abruptio placentae and intrauterine growth restriction (IUGR). Study Design: DNA was extracted from blood samples of 54 patients with placental vasculopathy (18 patients with abruptio placentae and 36 with IUGR) and 114 control patients and amplified by

Gabriël S. Gebhardt; Charlotte L. Scholtz; Renate Hillermann; Hein J. Odendaal

2001-01-01

12

The thermolabile variant of methylenetetrahydrofolate reductase (MTHFR) is not a major risk factor for neural tube defect in American Caucasians  

Microsoft Academic Search

Mutations in the gene for methylenetetrahydrofolate reductase (MTHFR) have been implicated as a risk factor in the formation\\u000a of neural tube defects. We investigated this gene in a series of 65 sporadic American Caucasians patients with lumbosacral\\u000a NTD and their unaffected parents, using both case-control design and assessment of linkage disequilibrium. We found no evidence\\u000a to support mutations in MTHFR

Marcy C. Speer; Gordon Worley; Joanne F. Mackey; Elizabeth Melvin; W. Jerry Oakes; Timothy M. George

1997-01-01

13

Association of Methylenetetrahydrofolate Reductase (MTHFR-677 and MTHFR-1298) Genetic Polymorphisms with Occlusive Artery Disease and Deep Venous Thrombosis in Macedonians  

PubMed Central

Aim To analyze the association of methylenetetrahydrofolate reductase polymorphisms (MTHFR-677 and MTHFR-1298) with occlusive artery disease and deep venous thrombosis in Macedonians. Methods We examined 83 healthy respondents, 76 patients with occlusive artery disease, and 67 patients with deep venous thrombosis. Blood samples were collected and DNA was isolated from peripheral blood leukocytes. Identification of MTHFR mutations was done with CVD StripAssay (ViennaLab, Labordiagnostika GmbH, Vienna, Austria) and the population genetics analysis package, PyPop, was used for the analysis. Pearson P values, crude odds ratio, and Wald’s 95% confidence intervals were calculated. Results The frequency of C alleles of MTHFR-677 was 0.575 in patients with deep venous thrombosis, 0.612 in patients with occlusive artery disease, and 0.645 in healthy participants. The frequency of T allele of MTHFR-677 was lower in healthy participants (0.355) than in patients with occlusive artery disease (0.388) and deep venous thrombosis (0.425). The frequency of A allele for MTHFR-1298 was 0.729 in healthy participants, 0.770 in patients with occlusive artery disease, and 0.746 in patients with deep venous thrombosis. The frequency of C allele of MTHFR-1298 was 0.271 in healthy participants, 0.230 in patients with occlusive artery disease, and 0.425 in patients with deep venous thrombosis. No association of MTHFR-677 and MTHFR-1289 polymorphisms with occlusive artery disease and deep venous thrombosis was found, except for the protective effect of MTHFR/CA:CC diplotype for occlusive artery disease. Conclusion We could not confirm a significant association of MTHFR-677 and MTHFR-1289 polymorphisms with occlusive artery disease or deep venous thrombosis in Macedonians, except for the protective effect of MTHFR/CA:CC diplotype against occlusive artery disease.

Spiroski, Igor; Kedev, Sashko; Antov, Slobodan; Arsov, Todor; Krstevska, Marija; Dzhekova-Stojkova, Sloboda; Kostovska, Stojanka; Trajkov, Dejan; Petlichkovski, Aleksandar; Strezova, Ana; Efinska-Mladenovska, Olivija; Spiroski, Mirko

2008-01-01

14

Methylenetetrahydrofolate reductase (MTHFR) deficiency enhances resistance against cytomegalovirus infection.  

PubMed

Folates provide one-carbon units for nucleotide synthesis and methylation reactions. A common polymorphism in the MTHFR gene (677C --> T) results in reduced enzymatic activity, and is associated with an increased risk for neural tube defects and cardiovascular disease. The high prevalence of this polymorphism suggests that it may have experienced a selective advantage under environmental pressure, possibly an infectious agent. To test the hypothesis that methylenetetrahydrofolate reductase (MTHFR) genotype influences the outcome of infectious disease, we examined the response of Mthfr-deficient mice against mouse cytomegalovirus (MCMV) infection. Acute MCMV infection of Mthfr(-/-) mice resulted in early control of cytokine secretion, decreased viral titer and preservation of spleen immune cells, in contrast to Mthfr wild-type littermates. The phenotype was abolished in MTHFR transgenic mice carrying an extra copy of the gene. Infection of primary fibroblasts with MCMV showed a decrease in viral replication and in the number of productively infected cells in Mthfr(+/-) fibroblasts compared with wild-type cells. These results indicate that Mthfr deficiency protects against MCMV infection in vivo and in vitro, suggesting that human genetic variants may provide an advantage in the host response against certain pathogens. PMID:19609317

Fodil-Cornu, N; Kozij, N; Wu, Q; Rozen, R; Vidal, S M

2009-07-16

15

Methylenetetrahydrofolate reductase (MTHFR) deficiency presenting as a rash.  

PubMed

We report on the case of a 2-year-old girl recently diagnosed with Methylenetetrahydrofolate reductase (MTHFR) deficiency who originally presented in the neonatal period with a distinctive rash. At 11 weeks of age she developed seizures, she had acquired microcephaly and developmental delay. The rash deteriorated dramatically following commencement of phenobarbitone; both rash and seizures abated following empiric introduction of pyridoxine and folinic acid as treatment of possible vitamin responsive seizures. We postulate that phenobarbitone in combination with MTHFR deficiency may have caused her rash to deteriorate and subsequent folinic acid was helpful in treating the rash and preventing further acute neurological decline as commonly associated with this condition. PMID:22848014

Crushell, Ellen; O'Leary, Daire; Irvine, Alan D; O'Shea, Anne; Mayne, Philip D; Reardon, William

2012-07-27

16

Homozygous C677T mutation in the MTHFR gene as an independent risk factor for multiple small-artery occlusions  

Microsoft Academic Search

Introduction: Hyperhomocysteinemia is an independent risk factor for cerebrovascular disease and the homozygous C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene can induce hyperhomocysteinemia. However, the association between this 677TT genotype and ischemic stroke still remains controversial. Therefore, we carried out this study to determine whether the MTHFR TT genotype is associated with certain subtypes of ischemic stroke. Materials and

B. O Choi; N. K Kim; S. H Kim; M. S Kang; S Lee; J. Y Ahn; O. J Kim; D Oh

2003-01-01

17

Mutations of the MTHFR gene (428C>T and [458G>T+459C>T]) markedly decrease MTHFR enzyme activity.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) is the only route for the synthesis of 5-methyltetrahydrofolate, which is utilized to convert homocysteine to methionine. In this study, we measured the enzyme activity of a mutant MTHFR that was detected in a patient with hyperhomocysteinemia. The 428C>T mutation in exon 2 of the MTHFR gene is a novel mutation, while the [458G>T+459C>T] mutation in exon 2 is a previously reported mutation. The activity of mutant enzymes containing the 428C>T, [458G>T+459C>T] and 677C>T mutations was 12.7+/-4.7%, 48.1+/-18.8%, and 43.6+/-14.4%, respectively, of that of the wild type enzyme. Our results suggest that these two variants each result in a severe MTHFR deficiency, which causes a developmental delay and cerebral vascular disease. PMID:15048559

Yano, Hidetaka; Nakaso, Kazuhiro; Yasui, Kenichi; Wakutani, Yosuke; Nakayasu, Hiroyuki; Kowa, Hisanori; Adachi, Yoshiki; Nakashima, Kenji

2004-03-27

18

A second common variant in the methylenetetrahydrofolate reductase (MTHFR) gene and its relationship to MTHFR enzyme activity, homocysteine, and cardiovascular disease risk.  

PubMed

Molecular defects in genes encoding enzymes involved in homocysteine metabolism may account for mild hyperhomocysteinemia, an independent and graded risk factor for cardiovascular disease (CVD). We examined the relationship of two polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, the 677C-->T and 1298A-->C variants, to MTHFR activity, homocysteine concentrations, and risk of CVD in a population of 190 vascular disease patients and 601 apparently healthy controls. The mean specific and residual MTHFR activities were significantly lower in 677CT and 677TT individuals (both P<0.001). The 1298A-->C mutation alone showed no effect on MTHFR activities. However, when the 677C-->T genotype was taken into account, the 1298A-->C mutation also caused a significant decrease in MTHFR activities, which was observed in both the homozygous 1298CC (P<0.001) and the heterozygous 1298AC states (P=0.005). Both the 677TT as the 677CT genotypes were associated with significantly higher fasting and postload homocysteine levels than 677CC (P<0.001 and P=0.003, respectively). The 1298A-->C mutation had no effect on fasting or postload homocysteine levels. Since homocysteine itself is considered to be positively associated with the risk of CVD, these findings indicate that the 1298A-->C mutation cannot be considered a major risk factor for CVD. PMID:11692165

Lievers, K J; Boers, G H; Verhoef, P; den Heijer, M; Kluijtmans, L A; van der Put, N M; Trijbels, F J; Blom, H J

2001-09-01

19

Bilateral transverse sinus thrombosis secondary to a homozygous C677T MTHFR gene mutation.  

PubMed

We describe the case of a previously healthy young man who presented with headache, diplopia, nausea, vomiting, and bilateral papilledema. Magnetic resonance venography of the brain revealed thrombosis of the right transverse sinus. Blood tests showed elevated homocysteine levels, and coagulation studies revealed a homozygous C677T mutation and a heterozygous A1298C mutation of the methylenetetrahydrofolate reductase (MTHFR) gene. The patient had no other etiology for venous thrombosis. We recommend screening patients who present with sinus thrombosis for MTHFR gene mutations. PMID:18666857

Kanaan, Ziad M; Mahfouz, Rami; Taher, Ali; Sawaya, Raja A

2008-09-01

20

The 1298A?C polymorphism in methylenetetrahydrofolate reductase (MTHFR): in vitro expression and association with homocysteine  

Microsoft Academic Search

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

Ilan S. Weisberg; Paul F. Jacques; Jacob Selhub; Andrew G. Bostom; Zhoutao Chen; R. Curtis Ellison; John H. Eckfeldt; Rima Rozen

2001-01-01

21

Metabolic effects of C677T and A1298C mutations at the MTHFR gene in Brazilian children with neural tube defects  

Microsoft Academic Search

Background: Methylenetetrahydrofolate reductase (MTHFR) deficiency leads to impairment in folate metabolism and is implicated as a risk factor for neural tube defects (NTDs). Both C677T and A1298C MTHFR mutations are associated with NTDs, in some populations. Methods: The frequencies of the C677T and A1298C MTHFR mutations were determined in 25 children with NTDs, case mothers and 75 healthy individuals from

Andrea L. A Cunha; Mario H Hirata; Chong A Kim; Elvira M Guerra-Shinohara; Kymio Nonoyama; Rosario D. C Hirata

2002-01-01

22

Maternal methylenetetrahydrofolate reductase (MTHFR) homozygosity and neonatal outcome: follow-up of 42 pregnancies at risk.  

PubMed

From February 2006 to March 2008, 42 pregnant women homozygous for the 677CT-methylenetetrahydrofolate reductase (MTHFR) allele were recruited in our obstetrics service for pregnancy at risk. All had antithrombotic prophylaxis with low-dose aspirin and/or low-molecular-weight heparin, supplemented with folic acid. In all, 2 women lost the fetus and 4 were lost to follow-up before delivery. A total of 36 women delivered term infants who all underwent transfontanellar ultrasonography within 24 hours of birth. Six (16.6%) had ischemic or hemorrhagic cerebral lesions. No differences were observed in gestational age, birth weight, or umbilical cord pH between the 30 healthy infants and the 6 with cerebral lesions. Neonatal outcomes were negative in spite of maternal folic acid supplementation and antithrombotic prophylaxis during pregnancy. This suggests a relationship between maternal homozygous mutation in the 677CT-MTHFR allele and neonatal cerebral lesions. PMID:20357240

Pogliani, Laura; Muggiasca, Luisa; Arrigoni, Luisa; Rossi, Edoardo; Zuccotti, Gianvincenzo

2010-03-31

23

Methylenetetrahydrofolate reductase gene mutations as risk factors for sudden hearing loss  

Microsoft Academic Search

Sudden hearing loss (SHL) can be caused by vascular disorders favoring impaired cochlear perfusion. Several inherited prothrombotic risk factors have been considered in the pathogenesis of vascular impairment, and the possible role of genetic alterations has recently been suggested. Methylenetetrahydrofolate reductase (MTHFR) gene mutations at nucleotides 677 and 1298 cause reduced MTHFR enzyme activity, which leads to increased homocysteine and

Pasquale Capaccio; Francesco Ottaviani; Valeria Cuccarini; Umberto Ambrosetti; Enrico Fagnani; Alessandro Bottero; Salvatore Cenzuales; Bruno Mario Cesana; Lorenzo Pignataro

2005-01-01

24

COMBINED MARGINAL FOLATE AND RIBOFLAVIN STATUS AFFECT HOMOCYSTEINE METHYLATION IN CULTURED IMMORTALIZED LYMPHOCYTES FROM PERSONS HOMOZYGOUS FOR THE MTHFR C677T MUTATION  

Technology Transfer Automated Retrieval System (TEKTRAN)

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the methyl donor for the synthesis of methionine from homocysteine. A common C677T mutation in the MTHFR gene renders the enzyme 50% less active than the wild-type enzym...

25

A Common Mutation A1298C in Human Methylenetetrahydrofolate Reductase Gene: Association with Plasma Total Homocysteine and Folate Concentrations1  

Microsoft Academic Search

Methylenetetrahydrofolate reductase (MTHFR) is one of the main regulatory enzymes of homocys- teine metabolism. Previous studies revealed that a common mutation in MTHFR gene C677T is related to hyperhomocysteinemia and occlusive vascular pathology. In the current study, we determined the prevalence of a newly described mutation in the human MTHFR gene A1298C, and the already known C677T mutation, and related

Gideon Friedman; Netta Goldschmidt; Yechiel Friedlander; Arie Ben-Yehuda; Jacob Selhub; Sharona Babaey; Malka Mendel; Miriam Kidron; Hanoch Bar-On

26

Identification of four novel mutations in severe methylenetetrahydrofolate reductase deficiency.  

PubMed

Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is an inborn error of folate metabolism, and is inherited as an autosomal recessive trait. MTHFR is a key enzyme in folate-dependent remethylation of homocysteine, and reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. Patients with this severe enzymatic deficiency are biochemically characterised by homocystinuria and hypomethioninaemia, and may suffer from neurological abnormalities, mental retardation and premature vascular disease. Here we report the molecular basis of severe MTHFR deficiency in four unrelated families from Turkish/Greek ancestry. By use of reverse-transcriptase (RT)-PCR, subsequently followed by direct sequencing analysis, we were able to identify four novel mutations in the MTHFR gene: two missense (983A-->G; 1027T-->G) and two nonsense (1084C-->T; 1711C-->T) mutations. Furthermore, a splice variant containing a premature termination codon, was observed in one patient, probably as a secondary effect of the 1027T-->G missense mutation. The ongoing identification and characterisation of mutations in the MTHFR gene will provide further insight into the heterogeneity of the clinical phenotype in severe MTHFR deficiency. PMID:9781030

Kluijtmans, L A; Wendel, U; Stevens, E M; van den Heuvel, L P; Trijbels, F J; Blom, H J

27

Homozygous MTHFR C677T gene mutation and recurrent stroke in an infant.  

PubMed

The role of homozygosity for the C677T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene as an independent risk factor for primary and recurrent stroke has been questioned, although recent data appear to be supportive. However, the association of homozygous C677T MTHFR mutation with silent brain infarctions in infancy has not been reported. The authors describe an 11-month-old male who had suffered a silent brain infarction followed by a symptomatic arterial stroke. The evaluation revealed mildly elevated homocysteine levels secondary to homozygous C677T alleles for MTHFR and iron deficiency anemia. An extensive evaluation for other causes of infarction was negative. We suggest that the mother's homozygous MTHFR status played a role in the early onset of stroke and that iron deficiency anemia may have contributed to the recurrence. The patient was treated with anticoagulation therapy, folic acid, and iron supplementation and has not had a recurrent event during 3 years of follow-up. This case provides further evidence that homozygous MTHFR mutation is a predisposing factor for early and recurrent pediatric stroke, including silent infarcts, especially in the presence of other risk factors. PMID:16814086

Garoufi, Anastasia J; Prassouli, Alexia A; Attilakos, Achilleas V; Voudris, Konstantinos A; Katsarou, Eustathia S

2006-07-01

28

The Association between Two Common Mutations C677T and A1298C in Human Methylenetetrahydrofolate Reductase Gene and the Risk for Diabetic Nephropathy in Type II Diabetic Patients1  

Microsoft Academic Search

Mutations of the methylenetetrahydrofolate reductase (MTHFR) gene have been shown to be associated with a predisposition to developing diabetic nephropathy (DN) in specific populations. The frequency of two MTHFR mutations, a recently described mutation in the human MTHFR gene A1298C and C677T, whose association with DN is already known, was determined in an Israeli Jewish population with type 2 diabetes

Vlad Shpichinetsky; Itamar Raz; Yechiel Friedlander; Neta Goldschmidt; Isaiah D. Wexler; Arie Ben-Yehuda; Gideon Friedman

29

Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and FOLFOX response in colorectal cancer patients  

PubMed Central

AIMS To test prospectively the predictive value of germinal gene polymorphisms related to fluorouracil (FU) and oxaliplatin (Oxa) pharmacodynamics on toxicity and responsiveness of colorectal cancer (CRC) patients receiving FOLFOX therapy. METHODS Advanced CRC patients (n= 117) receiving FOLFOX 7 therapy were enrolled. Gene polymorphisms relevant for FU [thymidylate synthase (TYMS, 28 bp repeats including the G?C mutation + 6 bp deletion in 3'UTR), methylenetetrahydrofolate reductase (MTHFR, 677C?T, 1298A?C), dihydropyrimidine deshydrogenase (IVS14+1G?A) and Oxa: glutathione S-transferase (GST) ? (105Ile?Val, 114Ala?Val), excision repair cross-complementing group 1 (ERCC1) (118AAT?AAC), ERCC2 (XPD, 751Lys?Gln) and XRCC1 (399Arg?Gln)] were determined (blood mononuclear cells). RESULTS None of the genotypes was predictive of toxicity. Response rate (54.7% complete response + partial response) was related to FU pharmacogenetics, with both 677C?T (P= 0.042) and 1298A?C (P= 0.004) MTHFR genotypes linked to clinical response. Importantly, the score of favourable MTHFR alleles (677T and 1298C) was positively linked to response, with response rates of 37.1, 53.3, 62.5 and 80.0% in patients bearing no, one, two or three favourable alleles, respectively (P= 0.040). Polymorphisms of genes related to Oxa pharmacodynamics showed an influence on progression-free survival, with a better outcome in patients bearing GST? 105 Val/Val genotype or XPD 751Lys-containing genotype (P= 0.054). CONCLUSIONS These results show that response to FOLFOX therapy in CRC patients may be driven by MTHFR germinal polymorphisms.

Etienne-Grimaldi, Marie-Christine; Milano, Gerard; Maindrault-Goebel, Frederique; Chibaudel, Benoist; Formento, Jean-Louis; Francoual, Mireille; Lledo, Gerard; Andre, Thierry; Mabro, May; Mineur, Laurent; Flesch, Michel; Carola, Elisabeth; de Gramont, Aimery

2010-01-01

30

Methylenetetrahydrofolate reductase mutations, a genetic cause for familial recurrent neural tube defects.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) gene mutations have been implicated as risk factors for neural tube defects (NTDs). The best-characterized MTHFR genetic mutation 677C?T is associated with a 2-4 fold increased risk of NTD if patient is homozygous for this mutation. This risk factor is modulated by folate levels in the body. A second mutation in the MTHFR gene is an A?C transition at position 1298. The 1298A?C mutation is also a risk factor for NTD, but with a smaller relative risk than 677C?T mutation. Under conditions of low folate intake or high folate requirements, such as pregnancy, this mutation could become of clinical importance. We present a case report with MTHFR genetic mutation, who presented with recurrent familial pregnancy losses due to anencephaly/NTDs. PMID:22754237

Yaliwal, Laxmi V; Desai, Rathnamala M

2012-01-01

31

Methylenetetrahydrofolate reductase mutations, a genetic cause for familial recurrent neural tube defects  

PubMed Central

Methylenetetrahydrofolate reductase (MTHFR) gene mutations have been implicated as risk factors for neural tube defects (NTDs). The best-characterized MTHFR genetic mutation 677C?T is associated with a 2–4 fold increased risk of NTD if patient is homozygous for this mutation. This risk factor is modulated by folate levels in the body. A second mutation in the MTHFR gene is an A?C transition at position 1298. The 1298A?C mutation is also a risk factor for NTD, but with a smaller relative risk than 677C?T mutation. Under conditions of low folate intake or high folate requirements, such as pregnancy, this mutation could become of clinical importance. We present a case report with MTHFR genetic mutation, who presented with recurrent familial pregnancy losses due to anencephaly/NTDs.

Yaliwal, Laxmi V.; Desai, Rathnamala M.

2012-01-01

32

Intermediate hyperhomocysteinemia resulting from compound heterozygosity of methylenetetrahydrofolate reductase mutations.  

PubMed Central

Four subjects with thermolabile methylenetetrahydrofolate reductase (MTHFR) were discovered among 16 "obligate" heterozygotes for severe MTHFR deficiency and their family members. All four subjects had less than 25% of normal mean MTHFR specific activity in lymphocyte extracts. Three of them with normal serum folate and cyanocobalamin had intermediate hyperhomocysteinemia, and one with high serum folate and cyanocobalamin had no excessive accumulation of serum homocysteine. The biochemical features in these four subjects are distinguishable from subjects homozygous for the thermolabile MTHFR, whose specific activity is approximately 50% of the normal mean, and from heterozygotes for severe MTHFR deficiency, in whom the enzyme is thermostable and has a specific activity of about 50% of the normal mean. We propose that these four subjects are genetic compounds of the allele for the severe mutation and the allele for thermolabile mutation of the MTHFR gene. It is postulated that subjects with this genetic compound are more susceptible to the development of intermediate hyperhomocysteinemia despite normal folate and B12 levels. Nonetheless, hyperhomocysteinemia due to this compound heterozygosity is correctable by oral folic acid therapy.

Kang, S S; Wong, P W; Bock, H G; Horwitz, A; Grix, A

1991-01-01

33

Intermediate hyperhomocysteinemia resulting from compound heterozygosity of methylenetetrahydrofolate reductase mutations.  

PubMed

Four subjects with thermolabile methylenetetrahydrofolate reductase (MTHFR) were discovered among 16 "obligate" heterozygotes for severe MTHFR deficiency and their family members. All four subjects had less than 25% of normal mean MTHFR specific activity in lymphocyte extracts. Three of them with normal serum folate and cyanocobalamin had intermediate hyperhomocysteinemia, and one with high serum folate and cyanocobalamin had no excessive accumulation of serum homocysteine. The biochemical features in these four subjects are distinguishable from subjects homozygous for the thermolabile MTHFR, whose specific activity is approximately 50% of the normal mean, and from heterozygotes for severe MTHFR deficiency, in whom the enzyme is thermostable and has a specific activity of about 50% of the normal mean. We propose that these four subjects are genetic compounds of the allele for the severe mutation and the allele for thermolabile mutation of the MTHFR gene. It is postulated that subjects with this genetic compound are more susceptible to the development of intermediate hyperhomocysteinemia despite normal folate and B12 levels. Nonetheless, hyperhomocysteinemia due to this compound heterozygosity is correctable by oral folic acid therapy. PMID:1998340

Kang, S S; Wong, P W; Bock, H G; Horwitz, A; Grix, A

1991-03-01

34

Mutation (677 C to T) in the methylenetetrahydrofolate reductase gene aggravates hyperhomocysteinemia in hemodialysis patients  

Microsoft Academic Search

Mutation 677 C to T in the methylenetetrahydrofolate reductase gene aggravates hyperhomocysteinemia in hemodialysis patients. Hyperhomocysteinemia is frequent in hemodialysis patients and represents an independent risk factor for vascular disease in these patients. Elevated total homocysteine (tHcy) plasma levels can result from defective remethyla-tion of Hcy to methionine due to decreased activity of the enzyme methylenetetrahydrofolate reductase (MTHFR). A genetic

Manuela Födinger; Christine Mannhalter; Gabriele Wölfl; Ingrid Pabinger; Eva Müller; Rainer Schmid; Walter H Hörl; Gere Sunder-Plassmann

1997-01-01

35

Methylenetetrahydrofolate Reductase C677T Mutation and Nonalcoholic Fatty Liver Disease  

Microsoft Academic Search

A mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is known as one of the causes of hyperhomocyteinemia. The\\u000a oxidation products of homocysteine can initiate lipid peroxidation, which has a central role in the pathogenesis of nonalcoholic\\u000a fatty liver disease (NAFLD). We aimed to assess the possible role of the MTHFR C677T mutation in the progression of simple\\u000a steatosis to an

Ender Serin; Mustafa Güçlü; F Belgin Ataç; Hasibe Verdi; Fazilet Kayaselçuk; Birol Özer; Banu Bilezikçi; U?ur Y?lmaz

2007-01-01

36

Case-control Study of methylenetetrahydrofolate reductase mutations and hyperhomocysteinemia and risk of stroke.  

PubMed

The association of factor V-Leiden and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C mutations with stroke was investigated in 118 patients with stroke and 120 control subjects. MTHFR 677TT (P < .001) and 1298CC (P < .001), but not factor V-Leiden (P = .179), genotypes were associated with stroke. The C677T but not A1298C MTHFR mutation was associated with elevated homocysteine levels in patients and control subjects. In addition to hypertension, the significant predictors for stroke were MTHFR 677CT and TT and A1298CC genotypes, together with hyperhomocysteinemia, indicating a synergistic effect of MTHFR mutations with elevated homocysteine and other risk factors in pathogenesis of stroke. PMID:19717029

Almawi, Wassim Y; Khan, Abdulmajeed; Al-Othman, Sara S; Bakhiet, Moiz

37

Folate and breast cancer: the role of polymorphisms in methylenetetrahydrofolate reductase (MTHFR)  

Microsoft Academic Search

Evidence is growing that low folate status may be a factor in the aetiology of several cancers, including breast cancer. The methylenetetrahydrofolate reductase gene (MTHFR), which has a key role in folate metabolism, is polymorphic. We report a case-control study of two functional polymorphisms in MTHFR, dietary folate intake and breast cancer. Sixty-two cases with invasive breast cancer and sixty-six

L Sharp; J Little; A. C Schofield; E Pavlidou; S. C Cotton; Z Miedzybrodzka; J. O. C Baird; N. E Haites; S. D Heys; D. A Grubb

2002-01-01

38

Methylenetetrahydrofolate Reductase (MTHFR) from Mediterranean to Sub-Saharan Areas  

Microsoft Academic Search

There are differences in the allele frequency of MTHFR polymorphism between Western and African population. The aim of this study is to determinate the prevalence of MTHFR C677T and A1298C polymorphisms in young and old people living in different areas from Mediterranean to sub- Saharan areas. The observed vs expected genotype frequencies of 677T were in Hardy Weinberg equilibrium, with

Rosa Chillemi; Andrea Angius; Ivana Persico; Alessandro Sassu; Dionigio A. Prodi; Salvatore Musumeci

2006-01-01

39

Folic acid rivals methylenetetrahydrofolate reductase (MTHFR) gene-silencing effect on MEPM cell proliferation and apoptosis  

Microsoft Academic Search

It's clear that environmental factors play a role in the aetiology of orofacial clefting (OFC) and an important area of future research will be to unravel interactions that occur between candidate genes and environmental factors during early development of the embryo. Periconceptional folic acid supplementation may reduce the risk of OFC. Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene reduce availability

Wen-lin Xiao; Min Wu; Bing Shi

2006-01-01

40

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

PubMed

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). PMID:7920641

Goyette, P; Sumner, J S; Milos, R; Duncan, A M; Rosenblatt, D S; Matthews, R G; Rozen, R

1994-06-01

41

Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and susceptibility to pediatric acute lymphoblastic leukemia in a German study population  

Microsoft Academic Search

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) has a major impact on the regulation of the folic acid pathway due to conversion of 5,10-methylenetetrahydrofolate (methylene-THF) to 5-methyl-THF. Two common polymorphisms (677C>T and 1298A>C) in the gene coding for MTHFR have been shown to reduce MTHFR enzyme activity and were associated with the susceptibility to different disorders, including vascular disease, neural tube defects and

Eckart Schnakenberg; Andrea Mehles; Gunnar Cario; Klaus Rehe; Kathrin Seidemann; Brigitte Schlegelberger; Holger A Elsner; Karl H Welte; Martin Schrappe; Martin Stanulla

2005-01-01

42

Methylenetetrahydrofolate reductase (MTHFR) variants and fluorouracil-based treatments in colorectal cancer.  

PubMed

5-fluorouracil (5FU)-based treatments remain the main chemotherapy for colorectal cancer. Optimal cytotoxicity of fluoropyrimidines requires elevated CH(2)FH(4) tumoral concentrations, controlled by the methylenetetrahydrofolate reductase (MTHFR) enzyme, which irreversibly converts CH(2)FH(4) into 5-methyltetrahydrofolate. The MTHFR gene is subject to several polymorphisms, of which the 677C>T and 1298A>C SNPs are the two most commonly linked with altered enzyme activity. Since a drop in MTHFR enzymatic activity may theoretically favor an increase in intracellular CH(2)FH(4) concentrations, it can be hypothesized that tumors exhibiting the rare MTHFR variants may be more sensitive to 5FU cytotoxicity. Accordingly, experimental data have shown that rare MTHFR variants in position 677 and 1298 are more sensitive to 5FU. However, results of clinical data do not concord regarding the influence of MTHFR genotype on tumoral CH(2)FH(4) concentration, 5FU responsiveness, patient survival and 5FU-related toxicity. These discrepancies may result from the interpatient variability arising from the individual folate status, as well as from the limited role of fluoropyrimidines in the current chemotherapy regimen administered in colorectal cancer. PMID:18034621

Etienne-Grimaldi, Marie-Christine; Francoual, Mireille; Formento, Jean-Louis; Milano, Gérard

2007-11-01

43

A second common variant in the methylenetetrahydrofolate reductase (MTHFR) gene and its relationship to MTHFR enzyme activity, homocysteine, and cardiovascular disease risk  

Microsoft Academic Search

Molecular defects in genes encoding enzymes involved in homocysteine metabolism may account for mild hyperhomocysteinemia, an independent and graded risk factor for cardiovascular disease (CVD). We examined the relationship of two polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, the 677CMT and 1298AMC variants, to MTHFR activity, homocysteine concentrations, and risk of CVD in a population of 190 vascular disease patients

Karin J. Lievers; Godfried H. Boers; Petra Verhoef; Martin Heijer; Leo A. Kluijtmans; Nathalie M. Put; Frans J. Trijbels; Henk J. Blom

2001-01-01

44

Polymorphisms in methylenetetrahydrofolate reductase gene ( MTHFR ) and the age of onset of sporadic colorectal adenocarcinoma  

Microsoft Academic Search

Background and aims  Evidence is accumulating for a role of folate in the aetiology of colorectal cancer (CRC). The methylenetetrahydrofolate reductase\\u000a (MTHFR) gene, involved in folate metabolism, is polymorphic in humans. Since it is unknown whether the MTHFR C677T and A1298C polymorphisms alter the risk for CRC, this was the aim of our study.\\u000a \\u000a \\u000a \\u000a Materials and methods  Genomic DNA from 102 sporadic

Carmen S. P. Lima; Helvia Nascimento; Luciana C. Bonadia; Maria T. Teori; Claudio S. R. Coy; Juvenal R. N. Góes; Fernando F. Costa; Carmen S. Bertuzzo

2007-01-01

45

Effect of methotrexate on the survival of human lymphocyte cultures carrying MTHFR 677 (C>T) and MTHFR 1298 (A>C) mutations.  

PubMed

The correlations between the presence of MTHFR 677 (C>T) and MTHFR 1298 (A>C) mutations in human lymphocytes and the sensitivity of lymphocytes to methotrexate (MTX) were examined in cultures derived from 82 unrelated women, genotyped for these mutations by polymerase chain reaction-restriction fragment length polymorphism. Lymphocytes heterozygous for the mutant allele, MTHFR 677T, were significantly more sensitive to methotrexate than those carrying the homozygous wild-type allele, MTHFR677C, and those carrying either the mutant or the wild-type alleles in the polymorphic MTHFR 1298 site. In addition, the lymphocyte cultures carrying the mutant MTHFR 1298C allele were not different in their sensitivity to MTX from those cultures carrying the wild-type allele, MTHFR 1298A. This demonstrated that the polymorphic site MTHFR C677, but not MTHFR1298, could be considered as a useful pharmacogenetic determinant in planning and designing the effective personal MTX chemotherapeutic doses and regimes. PMID:19514945

Al-Refai, Ekhlas A; Sadiq, May F; Khassawneh, Mohammad Y; Amjad D, Al-Nasser

2009-01-01

46

Association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and age of onset in schizophrenia.  

PubMed

Different lines of evidence indicate that methylenetetrahydrofolate reductase (MTHFR) functional gene polymorphisms, causative in aberrant folate-homocysteine metabolism, are associated with increased vulnerability to several heritable developmental disorders. Opposing views are expressed considering the possible association between MTHFR and susceptibility for schizophrenia. In order to evaluate if age of onset could explain some of this discrepancy we investigated the relationship between two functional MTHFR gene polymorphisms and age at onset in this disorder. Scandinavian patients (n = 820) diagnosed with schizophrenia, schizoaffective disorder, and schizophreniform disorder were investigated. Two functional MTHFR single nucleotide polymorphisms (SNPs; rs1801131 and rs1801133) were genotyped and the effect of MTHFR polymorphisms on the age of onset was examined with survival analysis. In an attempt to replicate the findings from the Scandinavian sample, the association between rs1801133 and age at onset was also analyzed in Chinese high-risk families, with two or more affected siblings (n = 243). Among the Scandinavian patients the functional MTHFR SNP rs1801133 (C677T) significantly affected age at onset of schizophrenia in a dose-dependent manner (P = 0.0015), with lower age of onset with increasing numbers of the mutant T-allele. There was no evidence of rs1801131 (A1298C) affecting age of onset in schizophrenia. Within the Chinese high-risk families carriers of the MTHFR 677T allele showed earlier age at onset than siblings being homozygous for the wild-type allele (P = 0.008). The MTHFR C677T polymorphism may play a role as a modifying factor for age of onset in schizophrenia. PMID:19746410

Vares, Maria; Saetre, Peter; Deng, Hong; Cai, Guiqing; Liu, Xiehe; Hansen, Thomas; Rasmussen, Henrik B; Werge, Thomas; Melle, Ingrid; Djurovic, Srdjan; Andreassen, Ole A; Agartz, Ingrid; Hall, Hĺkan; Terenius, Lars; Jönsson, Erik G

2010-03-01

47

MTHFR variants reduce the risk of G:C->A:T transition mutations within the p53 tumor suppressor gene in colon tumors.  

PubMed

5,10-Methylene-tetrahydrofolate reductase (MTHFR) is a key enzyme in folate-mediated 1-carbon metabolism. Reduced MTHFR activity has been associated with genomic DNA hypomethylation. Methylated cytosines at CpG sites are easily mutated and have been implicated in G:C-->A:T transitions in the p53 tumor suppressor gene. We investigated 2 polymorphisms in the MTHFR gene (C677T and A1298C) and their associations with colon tumor characteristics, including acquired mutations in Ki-ras and p53 genes and microsatellite instability (MSI). The study population comprised 1248 colon cancer cases and 1972 controls, who participated in a population-based case-control study and had been analyzed previously for MSI, acquired mutations in Ki-ras, p53, and germline MTHFR polymorphisms. Multivariable-adjusted odds ratios are presented. Overall, MTHFR genotypes were not associated with MSI status or the presence of any p53 or Ki-ras mutation. Individuals with homozygous variant MTHFR genotypes had a significantly reduced risk of G:C-->A:T transition mutations within the p53 gene, yet, as hypothesized, only at CpG-associated sites [677TT vs. 677CC (referent group) OR = 0.4 (95% CI: 0.1-0.8) for CpG-associated sites; OR = 1.5 (0.7-3.6) for non-CpG associated sites]. Genotypes conferring reduced MTHFR activity were associated with a decreased risk of acquired G:C-->A:T mutations within the p53 gene occurring at CpG sites. Consistent with evidence on the phenotypic effect of the MTHFR C677T variant, we hypothesize that this relation may be explained by modestly reduced genomic DNA methylation, resulting in a lower probability of spontaneous deamination of methylated cytosine to thymidine. These results suggest a novel mechanism by which MTHFR polymorphisms can affect the risk of colon cancer. PMID:16177213

Ulrich, C M; Curtin, K; Samowitz, W; Bigler, J; Potter, J D; Caan, B; Slattery, M L

2005-10-01

48

Intermediate hyperhomocysteinaemia and compound heterozygosity for the common variant c.677C>T and a MTHFR gene mutation.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the regulation of plasma homocysteine levels. MTHFR deficiency, an autosomal recessive disorder, results in homocystinuria and hypomethioninaemia and presents with highly variable symptoms affecting many organs but predominantly the central nervous system. The common polymorphism of the MTHFR gene, c.677C>T, a known risk factor for elevated plasma homocysteine levels, occurs frequently in the caucasian population. In this study we investigated three subjects with moderate hyperhomocysteinaemia (total plasma homocysteine 72 micromol/L in case 1 and 90 micromol/L in case 3, total non-protein-bound homocysteine 144-186 micromol/L in case 2) but different clinical presentation with no symptoms in case 1, muscle weakness at 17 years of age in case 2, and syncopes and cerebral convulsions at 18 years of age in case 3. Each subject was compound heterozygous for the c.677C>T polymorphism and a novel mutation of the MTHFR gene (case 1: c.883G>A [p.D291N]; case 2: c.1552_c.1553delGA [p.E514fsX536]; case 3: c.616C>T [p.P202S]). Moderately decreased fibroblast MTHFR activity was associated with severely reduced affinity for NADPH and increased sensitivity to inhibition by S-adenosylmethionine (AdoMet) in case 2, and with mild FAD responsiveness in case 3. In case 1, fibroblast MTHFR activity was normal but the sensitivity to inhibition by AdoMet was slightly reduced. This study indicates that the sequence alteration c.677C>T combined with severe MTHFR mutations in compound heterozygous state may lead to moderate biochemical and clinical abnormalities exceeding those attributed to the c.677TT genotype and might require in addition to folate substitution further therapy to normalize homocysteine levels. PMID:17457696

Rummel, T; Suormala, T; Häberle, J; Koch, H G; Berning, C; Perrett, D; Fowler, B

2007-04-25

49

Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review.  

PubMed

The authors performed a meta-analysis of studies examining the association between polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, including MTHFR C677T and A1298C, and common psychiatric disorders, including unipolar depression, anxiety disorders, bipolar disorder, and schizophrenia. The primary comparison was between homozygote variants and the wild type for MTHFR C677T and A1298C. For unipolar depression and the MTHFR C677T polymorphism, the fixed-effects odds ratio for homozygote variants (TT) versus the wild type (CC) was 1.36 (95% confidence interval (CI): 1.11, 1.67), with no residual between-study heterogeneity (I(2) = 0%)--based on 1,280 cases and 10,429 controls. For schizophrenia and MTHFR C677T, the fixed-effects odds ratio for TT versus CC was 1.44 (95% CI: 1.21, 1.70), with low heterogeneity (I(2) = 42%)--based on 2,762 cases and 3,363 controls. For bipolar disorder and MTHFR C677T, the fixed-effects odds ratio for TT versus CC was 1.82 (95% CI: 1.22, 2.70), with low heterogeneity (I(2) = 42%)-based on 550 cases and 1,098 controls. These results were robust to various sensitively analyses. This meta-analysis demonstrates an association between the MTHFR C677T variant and depression, schizophrenia, and bipolar disorder, raising the possibility of the use of folate in treatment and prevention. PMID:17074966

Gilbody, Simon; Lewis, Sarah; Lightfoot, Tracy

2006-10-30

50

Failure to confirm influence of Methyltetrahydrofolate reductase (MTHFR) polymorphisms on age at onset of Huntington disease  

PubMed Central

Background Huntington disease (HD) is a fully penetrant, autosomal dominantly inherited disorder associated with abnormal expansions of a stretch of perfect CAG repeats in the 5' part of the IT15 gene. The number of repeat units is highly predictive for the age at onset (AO) of the disorder. But AO is only modestly correlated with repeat length when intermediate HD expansions are considered. Recently, suggestive association has been reported between a single nucleotide polymorphism (SNP; rs1801131, also known as A1298C) in the methyltetrahydrofolate reductase (MTHFR) gene and AO of HD. 5,10-MTHFR is a key enzyme in the folate metabolism, diverting metabolites toward methylation reactions or nucleotide synthesis. Using part of a previously established study cohort plus additional patients and appropriate statistical methods, we reinvestigated two polymorphisms in the MTHFR gene, C677T and A1298C, as well as their association with AO in 167 HD patients. Results There was no statistically significant impact on AO for HD patients, neither of MTHFR SNPs nor of the combinations thereof. Conclusion Contrary to previously described evidence the A1298C polymorphism in the MTHFR gene does not appear to modulate AO of HD patients.

Hansen, Wiebke; Saft, Carsten; Andrich, Jurgen; Muller, Thomas; Wieczorek, Stefan; Epplen, Jorg T; Arning, Larissa

2005-01-01

51

Folate metabolism gene 5,10-methylenetetrahydrofolate reductase (MTHFR) is associated with ADHD in myelomeningocele patients.  

PubMed

The objective of this study was to examine the relation between the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene and behaviors related to attention- deficit/hyperactivity disorder (ADHD) in individuals with myelomeningocele. The rationale for the study was twofold: folate metabolizing genes, (e.g. MTHFR), are important not only in the etiology of neural tube defects but are also critical to cognitive function; and individuals with myelomeningocele have an elevated incidence of ADHD. Here, we tested 478 individuals with myelomeningocele for attention-deficit hyperactivity disorder behavior using the Swanson Nolan Achenbach Pelham-IV ADHD rating scale. Myelomeningocele participants in this group for whom DNAs were available were genotyped for seven single nucleotide polymorphisms (SNPs) in the MTHFR gene. The SNPs were evaluated for an association with manifestation of the ADHD phenotype in children with myelomeningocele. The data show that 28.7% of myelomeningocele participants exhibit rating scale elevations consistent with ADHD; of these 70.1% had scores consistent with the predominantly inattentive subtype. In addition, we also show a positive association between the SNP rs4846049 in the 3'-untranslated region of the MTHFR gene and the attention-deficit hyperactivity disorder phenotype in myelomeningocele participants. These results lend further support to the finding that behavior related to ADHD is more prevalent in patients with myelomeningocele than in the general population. These data also indicate the potential importance of the MTHFR gene in the etiology of the ADHD phenotype. PMID:23227261

Spellicy, Catherine J; Northrup, Hope; Fletcher, Jack M; Cirino, Paul T; Dennis, Maureen; Morrison, Alanna C; Martinez, Carla A; Au, Kit Sing

2012-12-05

52

Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency.  

PubMed

5-Methyltetrahydrofolate, the major form of folate in plasma, is a carbon donor for the remethylation of homocysteine to methionine. This form of folate is generated from 5,10-methylenetetrahydrofolate through the action of 5,10-methylenetetrahydrofolate reductase (MTHFR), a cytosolic flavoprotein. Patients with an autosomal recessive severe deficiency of MTHFR have homocystinuria and a wide range of neurological and vascular disturbances. We have recently described the isolation of a cDNA for MTHFR and the identification of two mutations in patients with severe MTHFR deficiency. We report here the characterization of seven novel mutations in this gene: six missense mutations and a 5' splice-site defect that activates a cryptic splice site in the coding sequence. We also present a preliminary analysis of the relationship between genotype and phenotype for all nine mutations identified thus far in this gene. A nonsense mutation and two missense mutations (proline to leucine and threonine to methionine) in the homozygous state are associated with extremely low activity (0%-3%) and onset of symptoms within the 1st year of age. Other missense mutations (arginine to cysteine and arginine to glutamine) are associated with higher enzyme activity and later onset of symptoms. PMID:7726158

Goyette, P; Frosst, P; Rosenblatt, D S; Rozen, R

1995-05-01

53

Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency.  

PubMed Central

5-Methyltetrahydrofolate, the major form of folate in plasma, is a carbon donor for the remethylation of homocysteine to methionine. This form of folate is generated from 5,10-methylenetetrahydrofolate through the action of 5,10-methylenetetrahydrofolate reductase (MTHFR), a cytosolic flavoprotein. Patients with an autosomal recessive severe deficiency of MTHFR have homocystinuria and a wide range of neurological and vascular disturbances. We have recently described the isolation of a cDNA for MTHFR and the identification of two mutations in patients with severe MTHFR deficiency. We report here the characterization of seven novel mutations in this gene: six missense mutations and a 5' splice-site defect that activates a cryptic splice site in the coding sequence. We also present a preliminary analysis of the relationship between genotype and phenotype for all nine mutations identified thus far in this gene. A nonsense mutation and two missense mutations (proline to leucine and threonine to methionine) in the homozygous state are associated with extremely low activity (0%-3%) and onset of symptoms within the 1st year of age. Other missense mutations (arginine to cysteine and arginine to glutamine) are associated with higher enzyme activity and later onset of symptoms. Images Figure 1 Figure 2

Goyette, P; Frosst, P; Rosenblatt, D S; Rozen, R

1995-01-01

54

Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency  

SciTech Connect

5-Methyltetrahydrofolate, the major form of folate in plasma, is a carbon donor for the remethylation of homocysteine to methionine. This form of folate is generated from 5,10-methylenetetrahydrofolate through the action of 5,10-methylenetetrahydrofolate reductase (MTHFR), a cytosolic flavoprotein. Patients with an autosomal recessive severe deficiency of MTHFR have homocystinuria and a wide range of neurological and vascular disturbances. We have recently described the isolation of a cDNA for MTHFR and the identification of two mutations in patients with severe MTHFR deficiency. We report here the characterization of seven novel mutations in this gene: six missense mutations and a 5{prime} splice-site defect that activates a cryptic splice in the coding sequence. We also present a preliminary analysis of the relationship between genotype and phenotype for all nine mutations identified thus far in this gene. A nonsense mutation and two missense mutations (proline to leucine and threonine to methionine) in the homozygous state are associated with extremely low activity (0%-3%) and onset of symptoms within the 1st year of age. Other missense mutations (arginine to cysteine and arginine to glutamine) are associated with higher enzyme activity and later onset of symptoms. 19 refs., 4 figs., 2 tabs.

Goyette, P.; Frosst, P.; Rosenblatt, D.S.; Rozen. R. [McGill Univ., Montreal (Canada)

1995-05-01

55

A1298C methylenetetrahydrofolate reductase mutation and coronary artery disease: relationships with C677T polymorphism and homocysteine\\/folate metabolism  

Microsoft Academic Search

5, 10-Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme in homocysteine\\/methionine metabolism. The most-studied\\u000a C677T polymorphism in the MTHFR gene results in a thermolabile variant with reduced activity, and is associated with increased\\u000a levels of total plasma homocysteine, a risk factor for coronary artery disease. A new mutation in the MTHFR gene (A1298C)\\u000a has also been reported to lower enzyme activity.

S. Friso; D. Girelli; E. Trabetti; C. Stranieri; O. Olivieri; E. Tinazzi; N. Martinelli; G. Faccini; P. F. Pignatti; R. Corrocher

2002-01-01

56

Association of Methylenetetrahydrofolate Reductase (MTHFR) Polymorphism with Bone Mineral Density in Postmenopausal Japanese Women  

Microsoft Academic Search

.   The pathogenesis of osteoporosis is controlled by genetic and environmental factors. Considering the high prevalence of osteoporosis\\u000a in homocystinuria, abnormal homocysteine metabolism would contribute to the pathogenesis of osteoporosis. It is known that\\u000a the polymorphism of methylenetetrahydrofolate reductase (MTHFR), the enzyme catalyzing the reduction of 5,10-methylenetetrahydrofolate\\u000a to 5-methyltetrahydrofolate, correlates with hyperhomocysteinemia. In this study, we examined the association of

M. Miyao; H. Morita; T. Hosoi; H. Kurihara; S. Inoue; S. Hoshino; M. Shiraki; Y. Yazaki; Y. Ouchi

2000-01-01

57

Prevalence of the C677T Methylenetetra- hydrofolate Reductase Mutation in Thai Patients with Deep Vein Thrombosis  

Microsoft Academic Search

We investigated the prevalence of a genetic variation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene (C677T) using polymerase chain reaction techniques in a sample of 500 general Thai population and among 40 unselected Thai patients with an objectively confirmed history of deep vein thrombosis (DVT). The prevalence of the mutated homozygous and heterozygous C677T MTHFR genotype in the group of 500

Pantep Angchaisuksiri; Sarinee Pingsuthiwong; Thanyachai Sura; Katcharin Aryuchai; Manisa Busabaratana; Vichai Atichartakarn

2000-01-01

58

Factor V gene G1691A mutation, prothrombin gene G20210A mutation, and MTHFR gene C677T mutation are not risk factors for pulmonary thromboembolism in Chinese population  

Microsoft Academic Search

A mutation in coagulant factor V gene, a substitution in the 3? untranslated region of prothrombin gene, and a variant in 5,10-methylenetetrahydrofolate reductase (MTHFR) gene have been reported to be related to venous thromboembolism in Caucasians, but this relationship remains in debate in other populations. In this case–control study, we aimed to determine the prevalence of these three mutations in

Yanhui Lu; Yanfen Zhao; Guozhang Liu; Xiaoling Wang; Zhihong Liu; Baiping Chen; Rutai Hui

2002-01-01

59

The Common Mutations C677T and A1298C in the Human Methylenetetrahydrofolate Reductase Gene Are Associated with Hyperhomocysteinemia and Cardiovascular Disease in Hemodialysis Patients  

Microsoft Academic Search

Background: Plasma total homocysteine (tHcy) level might be an important risk factor for the development of cardiovascular disease (CVD) in dialysis patients. While both renal failure and mutations of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene may result in hyperhomocysteinemia and CVD, the distinct roles of the thermolabile MTHFR mutation at nucleotide C677T and the more recently described mutation at nucleotide A1298C

Y. S. Haviv; V. Shpichinetsky; N. Goldschmidt; I. Abou Atta; A. Ben-Yehuda; G. Friedman

2002-01-01

60

Methylenetetrahydrofolate reductase C677T mutation and nonalcoholic fatty liver disease.  

PubMed

A mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is known as one of the causes of hyperhomocyteinemia. The oxidation products of homocysteine can initiate lipid peroxidation, which has a central role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). We aimed to assess the possible role of the MTHFR C677T mutation in the progression of simple steatosis to an advanced form of NAFLD. Thirty-four patients with NAFLD diagnosed by histologic analysis and 282 healthy controls were included in the study. The discrimination of nonalcoholic steatohepatitis (NASH) from another NAFLD was made by NAFLD activity score (NAS), and a NAS>or=5 was considered NASH. Patients with either NASH or nonalcoholic fatty liver (NAFL) and controls were evaluated for frequency of the MTHFR C677T mutation. The frequency of the MTHFR C677T mutation was 53.5% (CT, 44.7%; TT, 8.9%) in controls and 41.5% (CT, 37.7%; TT, 3.8%) in patients (odds ratio [OR], 0.62; 95% confidence interval [CI], 0.34-1.12). There was no statistical difference in the frequency of this genotype between patients with NAFL and those with NASH (36% [CT, 28%; TT, 8%] vs 46.4% [CT, 46.4; TT, 0%]; OR, 0.65; 95% CI, 0.22-1.96). According to this study, the MTHFR C677T mutation does not seem to be a risk factor for the progression of NAFL to NASH. PMID:17356914

Serin, Ender; Güçlü, Mustafa; Ataç, F Belgin; Verdi, Hasibe; Kayaselçuk, Fazilet; Ozer, Birol; Bilezikçi, Banu; Yilmaz, U?ur

2007-03-14

61

Neonatal and Fetal Methylenetetrahydrofolate Reductase Genetic Polymorphisms: An Examination of C677T and A1298C Mutations  

PubMed Central

Methylenetetrahydrofolate reductase (MTHFR) mutations are commonly associated with hyperhomocysteinemia, and, through their defects in homocysteine metabolism, they have been implicated as risk factors for neural tube defects and unexplained, recurrent embryo losses in early pregnancy. Folate sufficiency is thought to play an integral role in the phenotypic expression of MTHFR mutations. Samples of neonatal cord blood (n=119) and fetal tissue (n=161) were analyzed for MTHFR C677T and A1298C mutations to determine whether certain MTHFR genotype combinations were associated with decreased in utero viability. Mutation analysis revealed that all possible MTHFR genotype combinations were represented in the fetal group, demonstrating that 677T and 1298C alleles could occur in both cis and trans configurations. Combined 677CT/1298CC and 677TT/1298CC genotypes, which contain three and four mutant alleles, respectively, were not observed in the neonatal group (P=.0402). This suggests decreased viability among fetuses carrying these mutations and a possible selection disadvantage among fetuses with increased numbers of mutant MTHFR alleles. This is the first report that describes the existence of human MTHFR 677CT/1298CC and 677TT/1298CC genotypes and demonstrates their potential role in compromised fetal viability.

Isotalo, Phillip A.; Wells, George A.; Donnelly, James G.

2000-01-01

62

Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and susceptibility to pediatric acute lymphoblastic leukemia in a German study population  

PubMed Central

Background Methylenetetrahydrofolate reductase (MTHFR) has a major impact on the regulation of the folic acid pathway due to conversion of 5,10-methylenetetrahydrofolate (methylene-THF) to 5-methyl-THF. Two common polymorphisms (677C>T and 1298A>C) in the gene coding for MTHFR have been shown to reduce MTHFR enzyme activity and were associated with the susceptibility to different disorders, including vascular disease, neural tube defects and lymphoid malignancies. Studies on the role of these polymorphisms in the susceptibility to acute lymphoblastic leukemia (ALL) led to discrepant results. Methods We retrospectively evaluated the association of the MTHFR 677C>T and 1298A>C polymorphisms with pediatric ALL by genotyping a study sample of 443 ALL patients consecutively enrolled onto the German multicenter trial ALL-BFM 2000 and 379 healthy controls. We calculated odds ratios of MTHFR genotypes based on the MTHFR 677C>T and 1298A>C polymorphisms to examine if one or both of these polymorphisms are associated with pediatric ALL. Results No significant associations between specific MTHFR variants or combinations of variants and risk of ALL were observed neither in the total patient group nor in analyses stratified by gender, age at diagnosis, DNA index, immunophenotype, or TEL/AML1 rearrangement. Conclusion Our findings suggest that the MTHFR 677C>T and 1298A>C gene variants do not have a major influence on the susceptibility to pediatric ALL in the German population.

Schnakenberg, Eckart; Mehles, Andrea; Cario, Gunnar; Rehe, Klaus; Seidemann, Kathrin; Schlegelberger, Brigitte; Elsner, Holger A; Welte, Karl H; Schrappe, Martin; Stanulla, Martin

2005-01-01

63

A Second Common Mutation in the Methylenetetrahydrofolate Reductase Gene: An Additional Risk Factor for Neural-Tube Defects?  

Microsoft Academic Search

Summary Recently, we showed that homozygosity for the common 677(CrT) mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, causing thermolability of the enzyme, is a risk factor for neural-tube defects (NTDs). We now report on another mutation in the same gene, the 1298(ArC) mutation, which changes a glutamate into an alanine residue. This mutation destroys anMboII recognition site and has an

Fons Gabreëls; Erik M. B. Stevens; Jan A. M. Smeitink; Frans J. M. Trijbels; Tom K. A. B. Eskes; Lambert P. van den Heuvel; Henk J. Blom

1998-01-01

64

Severe arterial thrombophilia associated with a homozygous MTHFR gene mutation (A1298C) in a young man with Klinefelter syndrome.  

PubMed

Klinefelter syndrome (KS) is the most common sex chromosome disorder in men. It may be associated with an increased risk for venous thrombosis and thromboembolism, which is partially explained by hypofibrinolysis due to androgen deficiency. Additional genetic or acquired thrombophilic states have been shown in KS patients complicated with venous thrombosis as isolated case reports. Arterial thrombotic events had not been previously reported in KS. In this study, a young man with KS who developed acute arterial thrombosis during testosterone replacement therapy is presented. He was homozygous for the A1298C mutation of the methylenetetrahydrofolate reductase (MTHFR) gene. PMID:18160591

Ozbek, Mustafa; Oztürk, M Akif; Ureten, Kemal; Ceneli, Ozcan; Erdogan, Mehmet; Haznedaroglu, Ibrahim C

2007-12-26

65

Folate and breast cancer: the role of polymorphisms in methylenetetrahydrofolate reductase (MTHFR).  

PubMed

Evidence is growing that low folate status may be a factor in the aetiology of several cancers, including breast cancer. The methylenetetrahydrofolate reductase gene (MTHFR), which has a key role in folate metabolism, is polymorphic. We report a case-control study of two functional polymorphisms in MTHFR, dietary folate intake and breast cancer. Sixty-two cases with invasive breast cancer and sixty-six general practice controls participated. Women reporting the highest dietary folate intake had non-significantly reduced breast cancer risk (odds ratio (OR) = 0.49, 95% confidence interval (CI) 0.20-1.20). Risk was significantly lower for the 1298CC genotype compared to AA (OR = 0.24, 95% CI 0.06-0.97). Relative to compound wild-type subjects, compound heterozygotes had moderately reduced risk (OR = 0.47, 95% CI 0.11-1.92) and homozygote variants (677TT and/or 1298CC) greater reduced risk (OR = 0.26, 95% CI 0.07-0.96); the trend was statistically significant. Patterns in risk with regard to genotype and folate combinations are broadly similar those reported for colorectal neoplasia. The roles of MTHFR and folate in breast cancer aetiology are likely to be complex. PMID:12430180

Sharp, L; Little, J; Schofield, A C; Pavlidou, E; Cotton, S C; Miedzybrodzka, Z; Baird, J O C; Haites, N E; Heys, S D; Grubb, D A

2002-07-01

66

Haplotype analysis of the 5,10-methylenetetrahydrofolate reductase (MTHFR) c.1298A>C (E429A) polymorphism  

PubMed Central

Background The polymorphism 5,10-methylenetetrahydrofolate reductase (MTHFR) c.1298A>C is associated with various diseases. 45 DNA samples homozygous for the A allele and 40 DNA probes homozygous for the C allele were taken from healthy German subjects of white Caucasian origin to analyze the haplotype of the two MTHFR c.1298A>C alleles. Samples were genotyped for the polymorphism MTHFR c.677C>T and for the silent polymorphisms MTHFR c.129C>T, IVS2 533 G>A, c.1068C>T and IVS10 262C>G. Findings Haplotype construction revealed that the C-allele of MTHFR c.1298A>C was more frequently observed in cis with c.129T, IVS2 533A, c.677C, c.1068T, and IVS10 262 G than expected from normal distribution. Estimation of the most recent common ancestor with the DMLE + 2.3 program resulted in an estimated age of approximately 36,660 years of the MTHFR c.1298C allele. Conclusion Given that the era from 30,000 to 40,000 years ago is characterised by the spread of modern humans in Europe and that the prevalence of the MTHFR c.1298C allele is significantly higher in Central Europe in comparison to African populations, a selective advantage of MTHFR c.1298C could be assumed, e. g. by adaption to changes in the nutritional environment. The known founder ancestry of the T allele of MTHFR c.677C>T allele, together with the present data suggests that the MTHFR mutant alleles c.677T and 1298C arose from two independent ancestral alleles, that both confer a selective advantage.

2011-01-01

67

Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia  

PubMed Central

Low folate intake as well as alterations in folate metabolism as a result of polymorphisms in the enzyme methylenetetrahydrofolate reductase (MTHFR) have been associated with an increased incidence of neural tube defects, vascular disease, and some cancers. Polymorphic variants of MTHFR lead to enhanced thymidine pools and better quality DNA synthesis that could afford some protection from the development of leukemias, particularly those with translocations. We now report associations of MTHFR polymorphisms in three subgroups of pediatric leukemias: infant lymphoblastic or myeloblastic leukemias with MLL rearrangements and childhood lymphoblastic leukemias with either TEL-AML1 fusions or hyperdiploid karyotypes. Pediatric leukemia patients (n = 253 total) and healthy newborn controls (n = 200) were genotyped for MTHFR polymorphisms at nucleotides 677 (C?T) and 1,298 (A?C). A significant association for carriers of C677T was demonstrated for leukemias with MLL translocations (MLL+, n = 37) when compared with controls [adjusted odd ratios (OR) = 0.36 with a 95% confidence interval (CI) of 0.15–0.85; P = 0.017]. This protective effect was not evident for A1298C alleles (OR = 1.14). In contrast, associations for A1298C homozygotes (CC; OR = 0.26 with a 95% CI of 0.07–0.81) and C677T homozygotes (TT; OR = 0.49 with a 95% CI of 0.20–1.17) were observed for hyperdiploid leukemias (n = 138). No significant associations were evident for either polymorphism with TEL-AML1+ leukemias (n = 78). These differences in allelic associations may point to discrete attributes of the two alleles in their ability to alter folate and one-carbon metabolite pools and impact after DNA synthesis and methylation pathways, but should be viewed cautiously pending larger follow-up studies. The data provide evidence that molecularly defined subgroups of pediatric leukemias have different etiologies and also suggest a role of folate in the development of childhood leukemia.

Wiemels, Joseph L.; Smith, Rosalyn N.; Taylor, G. Malcolm; Eden, Osborn B.; Alexander, Freda E.; Greaves, Mel F.

2001-01-01

68

Characterization of mutations in severe methylenetetrahydrofolate reductase deficiency reveals an FAD-responsive mutation.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) synthesizes 5-methyltetrahydrofolate, a major methyl donor for homocysteine remethylation to methionine. Severe MTHFR deficiency results in marked hyperhomocysteinemia and homocystinuria. Patients display developmental delay and a variety of neurological and vascular symptoms. Cloning of the human cDNA and gene has enabled the identification of 29 rare mutations in homocystinuric patients and two common variants [677C>T (A222V) and 1298A>C (E429A)] with mild enzymatic deficiency. Homozygosity for 677C>T or combined heterozygosity for both polymorphisms is associated with mild hyperhomocysteinemia. In this communication, we describe four novel mutations in patients with homocystinuria: two missense mutations (471C>G, I153M; 1025T>C, M338T), a nonsense mutation (1274G>A, W421X), and a 2-bp deletion (1553delAG). We expressed the 1025T>C mutation as well as two previously reported amino acid substitutions [983A>G (N324S) and 1027T>G (W339G)] and observed decreased enzyme activity at 10%, 36%, and 21% of control levels, respectively, with little or no effect on affinity for 5-methyltetrahydrofolate. One of these mutations, 983A>G (N324S), showed flavin adenine dinucleotide (FAD) responsiveness in vitro. Expression of these mutations in cis with the 677C>T polymorphism, as observed in the patients, resulted in an additional 50% decrease in enzyme activity. This report brings the total to 33 severe mutations identified in patients with severe MTHFR deficiency. PMID:12673793

Sibani, Sahar; Leclerc, Daniel; Weisberg, Ilan S; O'Ferrall, Erin; Watkins, David; Artigas, Carmen; Rosenblatt, David S; Rozen, Rima

2003-05-01

69

Methylenetetrahydrofolate reductase gene mutations as risk factors for sudden hearing loss.  

PubMed

Sudden hearing loss (SHL) can be caused by vascular disorders favoring impaired cochlear perfusion. Several inherited prothrombotic risk factors have been considered in the pathogenesis of vascular impairment, and the possible role of genetic alterations has recently been suggested. Methylenetetrahydrofolate reductase (MTHFR) gene mutations at nucleotides 677 and 1298 cause reduced MTHFR enzyme activity, which leads to increased homocysteine and reduced serum folate levels that are known to be involved in vascular impairment. We studied the relationship between SHL and MTHFR C677T and A1298C gene polymorphisms in 67 patients with SHL and 134 controls. Wild-type MTHFR CC677/AA1298 was significantly more frequent in the controls (P = .05), and gene mutations were significantly more frequent in the patients (P = .001; P = .001 for trend). Fifty-three patients (79.1%) and 56 controls (41.8%) (P = .012) had a double mutation (homozygosis 677TT or 1298CC; compound heterozygosis for both polymorphisms). Homocysteine levels were significantly higher and serum folate levels significantly lower in the patients than in the controls (P < .0001). These data suggest that MTHFR gene polymorphisms may be involved in the pathogenesis of SHL. PMID:16275406

Capaccio, Pasquale; Ottaviani, Francesco; Cuccarini, Valeria; Ambrosetti, Umberto; Fagnani, Enrico; Bottero, Alessandro; Cenzuales, Salvatore; Cesana, Bruno Mario; Pignataro, Lorenzo

70

Infertility in 5,10-methylenetetrahydrofolate reductase (MTHFR)-deficient male mice is partially alleviated by lifetime dietary betaine supplementation.  

PubMed

Metabolism of folate is essential for proper cellular function. Within the folate pathway, methylenetetrahydrofolate reductase (MTHFR) reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a methyl donor for remethylation of homocysteine to methionine, the precursor of S-adenosylmethionine. S-adenosylmethionine is the methyl donor for numerous cellular reactions. In adult male mice, MTHFR levels are highest in the testis; this finding, in conjunction with recent clinical evidence, suggest an important role for MTHFR in spermatogenesis. Indeed, we show here that severe MTHFR deficiency in male mice results in abnormal spermatogenesis and infertility. Maternal oral administration of betaine, an alternative methyl donor, throughout pregnancy and nursing, resulted in improved testicular histology in Mthfr-/- offspring at Postnatal Day 6, but not at 8 mo of age. However, when betaine supplementation was maintained postweaning, testicular histology improved, and sperm numbers and fertility increased significantly. We postulate that the adverse effects of MTHFR deficiency on spermatogenesis, may, in part, be mediated by alterations in the transmethylation pathway and suggest that betaine supplementation may provide a means to bypass MTHFR deficiency and its adverse effects on spermatogenesis by maintaining normal methylation levels within male germ cells. PMID:15548731

Kelly, Tamara L J; Neaga, Oana R; Schwahn, Bernd C; Rozen, Rima; Trasler, Jacquetta M

2004-11-17

71

Risk of colorectal cancer associated with the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in the Kashmiri population.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate metabolism and is involved in DNA synthesis, DNA repair and DNA methylation. The two common functional polymorphisms of MTHFR, 677 C?T and 1298 A?C, have been shown to impact various diseases, including cancer. The 677 C?T polymorphism has been widely investigated in different cancers and has been implicated as a risk factor for the development of various cancers. We investigated MTHFR C677T genotype frequency in colorectal cancer cases in the Kashmiri population and correlated this information with the known clinicopathological characters of colorectal cancer, in a case-control study. Eighty-six colorectal cancer cases were studied for MTHFR C677T polymorphism, compared to 160 controls taken from the general population, employing the PCR-RFLP technique. We found the frequency of the three different genotypes of MTHFR in our ethnic Kashmir population, i.e., CC, CT and TT, to be 68.6, 20.9 and 10.4% among colorectal cancer cases and 75.6, 16.9 and 7.5% among the general control population, respectively. There was a significant association between the MTHFR TT genotype and colorectal cancer in the higher age group. We conclude that the MTHFR C677T polymorphism slightly increases the risk for colorectal cancer development in our ethnic Kashmir population. PMID:21732284

Sameer, A S; Shah, Z A; Nissar, S; Mudassar, S; Siddiqi, M A

2011-06-21

72

Methylenetetrahydrofolate reductase (MTHFR) C677T genetic polymorphism and late infarct-related coronary artery patency after thrombolysis.  

PubMed

In patients with acute myocardial infarction (AMI), a persistently occluded infarct-related artery (IRA) is associated with unfavorable prognosis and genetic factors may be contributing factors to thrombolysis failure. One-hundred and one consecutive patients treated with intravenous thrombolysis during AMI were blind-tested for methylenetetrahydrofolate reductase (MTHFR) and circulating homocysteine levels and underwent protocol angiography 14 +/- 6 days after the event. IRA was patent in 61 patients and occluded in 40. Overall MTHFR 677TT frequency was 22%. Patients with MTHFR 677TT homozygosis had higher prevalence of occluded IRA (73%) versus those with MTHFR 677CT/CC genotype (30%, P < 0.001); MTHFR 677TT genotype predicted independently the risk of IRA occlusion with a specificity of 90% (odds ratio 3.8, 95% confidence interval 1.1-9.1; P = 0.03). Moreover, patients with occluded IRA and MTHFR 677TT genotype had the highest homocysteine levels (21 +/- 7.6 micromol/l vs. < or =14.9 +/- 3.8 micromol/l; P = 0.011). In patients with AMI, MTHFR 677TT homozygosis is independently associated with a persistently occluded IRA after thrombolysis. This finding may have pathophysiological and therapeutic implications for recanalization strategies in patients with AMI. PMID:18574671

Patti, Giuseppe; Fossati, Carolina; Nusca, Annunziata; Mega, Simona; Pasceri, Vincenzo; D'Ambrosio, Andrea; Giannetti, Barbara; Annibali, Ombretta; Avvisati, Giuseppe; Di Sciascio, Germano

2008-06-25

73

Methylenetetrahydrofolate reductase gene C677T mutation and plasma homocysteine level in Behçet's disease  

Microsoft Academic Search

Objective The aim of this study was to assess whether homozygosity for the 5, 10-methylenetetrahydrofolate reductase (MTHFR) C677T mutation and plasma homocysteine concentration are related to deep vein thrombosis in Behçet's disease (BD) patients. Methods Forty BD patients (23 males, 17 females; mean age 40.2±8.4 years) and 60 healthy controls (HC) (34 males, 26 females; mean age 41.6±6.9 years) were

Abdullah Canataroglu; Kahraman Tanriverdi; Tamer Inal; Gulsah Seydaoglu; Didem Arslan; Suleyman Ozbek; Fikri Baslamisli

2003-01-01

74

Methylenetetrahydrofolate reductase (MTHFR-677 and MTHFR-1298) genotypes and haplotypes and plasma homocysteine levels in patients with occlusive artery disease and deep venous thrombosis.  

PubMed

The aim was to investigate different genotypes and haplotypes of methylenetetrahydrofolate reductase (MTHFR-677, -1298) and plasma concentration of total homocysteine (tHcy) in Macedonian patients with occlusive artery disease (OAD) and deep venous thrombosis (DVT). Investigated groups consists of 80 healthy, 74 patients with OAD, and 63 patients with DVT. Plasma tHcy was measured with Microplate Enzyme Immunoassay. Identification of MTHFR genotypes and haplotypes was done with CVD StripAssay. The probability level (P-value) was evaluated by the Student's t-test. Plasma concentration of tHcy in CC and CT genotypes of MTHFR C677T was significantly increased in patients with OAD and in patients with DVT. Plasma concentration of tHcy in AC genotype of MTHFR A1298C was increased in patients with OAD and in patients with DVT. Plasma concentration of tHcy was significantly increased in AA genotype of patients with OAD, but not in patients with DVT. We found a significant increase of plasma tHcy in patients with OAD in comparison with healthy respondents for normal:heterozygote (CC:AC), heterozygote:normal (CT:AA), and heterozygote:heterozygote (CT:AC) haplotypes. Plasma concentration of tHcy in patients with DVT in comparison with healthy respondents was significantly increased for normal:normal (CC:AA), normal heterozygote (CC:AC), and heterozygote:heterozygote (CT:AC) haplotypes. We conclude that MTHFR C677T and MTHFR A1289C genotypes and haplotypes are connected with tHcy plasma levels in Macedonian patients with OAD and DVT. PMID:18800176

Spiroski, Igor; Kedev, Sashko; Antov, Slobodan; Arsov, Todor; Krstevska, Marija; Dzhekova-Stojkova, Sloboda; Bosilkova, Gordana; Kostovska, Stojanka; Trajkov, Dejan; Petlichkovski, Aleksandar; Strezova, Ana; Efinska-Mladenovska, Olivija; Spiroski, Mirko

2008-09-18

75

Methylenetetrahydrofolate reductase gene polymorphisms are associated with ischemic and hemorrhagic stroke: Dual effect of MTHFR polymorphisms C677T and A1298C  

Microsoft Academic Search

Hyperhomocysteinemia is an independent risk factor for ischemic stroke. The enzyme methylenetetrahydrofolate reductase (MTHFR) plays a critical role in modulating the levels of plasma homocysteine. Two polymorphisms in the MTHFR gene, C677T, A1298C result in reduced enzyme activity. The mechanisms of ischemic and hemorrhagic stroke are not well understood. Although controversial, previous studies have shown evidence of causality of both

Ali Sazci; Emel Ergul; Nese Tuncer; Gurler Akpinar; Ihsan Kara

2006-01-01

76

Association between the methylene tetrahydrofolate reductase gene C677T mutation and colchicine unresponsiveness in Behcet's disease  

PubMed Central

Purpose Behcet’s disease (BD) is a multisystemic immunoinflammatory disorder characterized by mucocutaneous, ocular, vascular, and central nervous system manifestations. The common methylene tetrahydrofolate reductase (MTHFR) gene C677T mutation is a known risk factor for thrombosis. The aim of this study was to investigate the MTHFR gene C677 mutation in patients with BD and evaluate if there was an association with clinical features, especially thrombosis, in a relatively large cohort of patients with BD. Methods The study included 318 patients with BD and 207 healthy controls. Genomic DNA was isolated and genotyped using PCR-based restriction fragment length polymorphism assay for the MTHFR gene C677T mutation. Results The genotype and allele frequencies of the C677T mutation showed a statistically significant difference between BD patients and controls (p=0.003 and p=0.001, respectively). There was also a significant association between C677T alteration and response to colchicine in BD patients (p=0.046). Conclusions The results of this study showed that there was a high association between the MTHFR gene C677T mutation and BD. Stratification analysis according to clinical features for this disease did not reveal an association except response to colchicine that was shown to be influenced by the MTHFR C677T mutation.

Yigit, Serbulent; Kalkan, Goknur; Rustemoglu, Aydin; Inanir, Ahmet; Gul, Ulker; Pancar, Gunseli Sefika; Akkanet, Songul; Ates, Omer

2012-01-01

77

The number of dichorionic twin pregnancies is reduced by the common MTHFR 677C-->T mutation.  

PubMed

In multiple pregnancies, demands for folic acid are considerably increased. The most common inborn error of folate metabolism is mild methylenetetrahydrofolate reductase (MTHFR) deficiency due to the synthesis of a thermolabile variant of the enzyme with impaired catalytic activity which leads to reduced 5-methyltetrahydrofolate (5-methyl-THF) and mildly elevated homocysteine plasma concentrations when folate status is inadequate. To investigate whether the number of offspring is influenced by this mutation, we determined the frequency of the 677C-->T substitution in 156 singleton and 40 twin mothers with dichorionic placentation. The T allele frequency in singleton (0.30) and twin mothers (0.16) was significantly different (P = 0.011). Mothers with the 677C-->T mutation had a 2.28 times lower risk of having a twin pregnancy than those without (95% confidence interval = 1.18-4.66; P = 0.008). Our observation would explain, at least in part, the hereditary trait of multiple gestations and is in agreement with the ethnic distribution pattern of the T allele which has been found to be inversely correlated with the incidence of dichorionic twins. Our findings suggest that the MTHFR 677C-->T mutation interferes with human brood size, probably by influencing the proliferation of rapidly dividing embryonic and maternal cells. PMID:11098041

Hasbargen, U; Lohse, P; Thaler, C J

2000-12-01

78

Seven novel mutations at the 5,10-methylenetetrahydrofolate reductase locus  

SciTech Connect

5,10-methylenetetrahydrofolate reductase (MTHFR), a flavoprotein, catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cofactor for methionine synthase in the methylation of homocysteine to methionine. Severe MTHFR deficiency, which causes homocysteinemia, is an autosomal recessive disorder with variable clinical features; developmental delay, perinatal death, mental retardation and asymptomatic individuals have been observed. A milder deficiency has been reported in patients with cardiovascular disease. We have recently described the isolation of a cDNA for MTHFR and the identification of 2 mutations in patients with severe MTHFR deficiency. We report here the characterization of 7 additional mutations at this locus: 5 missense mutations and 2 splicing mutations. Mutation analysis was performed by SSCP on PCR products generated either from reverse transcription-PCR of patients` total fibroblast RNA or from PCR of patients` genomic DNA. The 5 missense mutations are as follows: 1 Arg to Cys substitution in a hydrophilic segment proposed to be the hinge region that connects the catalytic and regulatory domains, 2 different Arg to Cys substitutions in 2 patients whose enzymatic thermolability is responsive to FAD, 1 Thr to Met substitution affecting an evolutionarily-conserved residue and a Pro to Leu substitution. The 2 splicing mutations affect the 5{prime} splice site and the 3{prime} splice site of 2 introns, respectively. The 5{prime} splice site mutation generates a 57 bp in-frame deletion of the RNA through the utilization of a cryptic 5{prime} splice site within the coding sequence. The identification of 9 mutations at this locus has allowed us to make preliminary correlations between genotype and phenotype and to contribute to a structure:function analysis of the enzyme.

Goyette, P.; Frosst, P.; Rosenblatt, D.S.; Rozen, R. [McGill Univ., Montreal (Canada)

1994-09-01

79

Methylenetetrahydrofolate Reductase Gene Variant (MTHFR C677T) and Migraine: A Case Control Study and Meta-analysis  

PubMed Central

Background Migraine is a common disorder that often coexists with depression. While a functional polymorphism in methyleneterahydrofolate reductase gene (MTHFR C677T) has been implicated in depression; the evidence to support an association of MTHFR with migraine has been inconclusive. We aim to investigate the effect of this variant on propensity for migraine and to perform a systematic review and meta-analysis of studies of MTHFR and migraine to date. Methods Individuals with migraine (n = 447) were selected from the Depression Case Control (DeCC) study to investigate the association between migraine and MTHFR C677T single nucleotide polymorphism (SNP) rs1801133 using an additive model compared to non-migraineurs adjusting for depression status. A meta-analysis was performed and included 15 studies of MTHFR and migraine. Results MTHFR C677T polymorphism was associated with migraine with aura (MA) (OR 1.31, 95% CI 1.01-1.70, p = 0.039) that remained significant after adjusting for age, sex and depression status. A meta-analysis of 15 case-control studies showed that T allele homozygosity is significantly associated with MA (OR = 1.42; 95% CI, 1.10-1.82) and total migraine (OR = 1.37; 95% CI, 1.07-1.76), but not migraine without aura (OR = 1.16; 95% CI, 0.36-3.76). In studies of non-Caucasian population, the TT genotype was associated with total migraine (OR= 3.46; 95% CI, 1.22-9.82), whereas in studies of Caucasians this variant was associated with MA only (OR = 1.28; 95% CI, 1.002-1.63). Conclusions MTHFR C677T is associated with MA in individuals selected for depression study. A meta-analysis of 15 studies supports this association and demonstrated effects across ethnic groups.

2011-01-01

80

Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms resulting in suboptimal oocyte maturation: a discussion of folate status, neural tube defects, schizophrenia, and vasculopathy.  

PubMed

Several conditions apparent at birth, e.g., neural tube defects (NTDs) and cardiac anomalies, are associated with polymorphisms in folate-related genes, such as the 677C --> T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene. Similar associations have been established for several constitutional chronic diseases in adulthood, such as schizophrenia, cardiovascular diseases, dementia, and even neoplasias in different organ systems. This spectrum of developmental anomalies and constitutional diseases may be linked to high-risk conceptions related to preovulatory overripeness ovopathy (PrOO). Some developmental anomalies, such as NTDs, are to a large extent prevented by supplementation of folic acid before conception, but supplementation does not seem to prevent cardiovascular disease or cognitive decline. These diverging results can be elucidated by introduction of the PrOO concept, as MTHFR polymorphisms and inherent low folate levels induce both non-optimal maturation of the oocyte and unsuccessful DNA methylation and demethylation, i.e. epigenetic mutations. The PrOO concept is testable and predicts in a random population the following: (1) female carriers of specific genetic MTHFR variants exhibit more ovulatory disturbances and inherent subfecundity traits, (2) descendents from a carrier mother, when compared with those from a wild-type mother, are more frequently conceived in PrOO high-risk conditions and, thus, (3) disadvantaged in life expectancy. If so, some MTHFR polymorphisms represent a novel, genetically determined, PrOO high-risk conception category comparable to those which are environmentally and behaviorly influenced. These high-risk conditions may cause developmental anomalies and defective epigenetic reprogramming in progeny. The interaction between genetic and environmental factors is a plausible mechanism of multifactorial inheritance. PMID:18616826

Jongbloet, Piet Hein; Verbeek, André Lm; den Heijer, Martin; Roeleveld, Nel

2008-07-10

81

Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms resulting in suboptimal oocyte maturation: a discussion of folate status, neural tube defects, schizophrenia, and vasculopathy  

PubMed Central

Several conditions apparent at birth, e.g., neural tube defects (NTDs) and cardiac anomalies, are associated with polymorphisms in folate-related genes, such as the 677C ? T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene. Similar associations have been established for several constitutional chronic diseases in adulthood, such as schizophrenia, cardiovascular diseases, dementia, and even neoplasias in different organ systems. This spectrum of developmental anomalies and constitutional diseases may be linked to high-risk conceptions related to preovulatory overripeness ovopathy (PrOO). Some developmental anomalies, such as NTDs, are to a large extent prevented by supplementation of folic acid before conception, but supplementation does not seem to prevent cardiovascular disease or cognitive decline. These diverging results can be elucidated by introduction of the PrOO concept, as MTHFR polymorphisms and inherent low folate levels induce both non-optimal maturation of the oocyte and unsuccessful DNA methylation and demethylation, i.e. epigenetic mutations. The PrOO concept is testable and predicts in a random population the following: (1) female carriers of specific genetic MTHFR variants exhibit more ovulatory disturbances and inherent subfecundity traits, (2) descendents from a carrier mother, when compared with those from a wild-type mother, are more frequently conceived in PrOO high-risk conditions and, thus, (3) disadvantaged in life expectancy. If so, some MTHFR polymorphisms represent a novel, genetically determined, PrOO high-risk conception category comparable to those which are environmentally and behaviorly influenced. These high-risk conditions may cause developmental anomalies and defective epigenetic reprogramming in progeny. The interaction between genetic and environmental factors is a plausible mechanism of multifactorial inheritance.

Jongbloet, Piet Hein; Verbeek, Andre LM; den Heijer, Martin; Roeleveld, Nel

2008-01-01

82

Methylenetetrahydrofolate reductase (MTHFR) C677T genetic polymorphism and late infarct-related coronary artery patency after thrombolysis  

Microsoft Academic Search

In patients with acute myocardial infarction (AMI), a persistently occluded infarct-related artery (IRA) is associated with\\u000a unfavorable prognosis and genetic factors may be contributing factors to thrombolysis failure. One-hundred and one consecutive\\u000a patients treated with intravenous thrombolysis during AMI were blind-tested for methylenetetrahydrofolate reductase (MTHFR)\\u000a and circulating homocysteine levels and underwent protocol angiography 14 ± 6 days after the event. IRA was patent

Giuseppe Patti; Carolina Fossati; Annunziata Nusca; Simona Mega; Vincenzo Pasceri; Andrea D’Ambrosio; Barbara Giannetti; Ombretta Annibali; Giuseppe Avvisati; Germano Di Sciascio

2009-01-01

83

C677T and A1298C Mutations in the MTHFR Gene and Survival in Colorectal Cancer  

Microsoft Academic Search

Background and aims: Our preliminary results laboratory have shown some association between C677T and A1298C MTHFR mutations and factors influencing survival in colorectal cancer. We studied the survival of patients with colorectal cancer depending on the initial Dukes- MAC stage of the disease at the time of diagnosis and the MTHFR mutation present. Methods: We randomly selected 69 patients with

Gelu Osian; Lucia Procopciuc; Liviu Vlad; Cornel Iancu; Teodora Mocan; Lucian Mocan

84

A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?  

PubMed Central

Recently, we showed that homozygosity for the common 677(C-->T) mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, causing thermolability of the enzyme, is a risk factor for neural-tube defects (NTDs). We now report on another mutation in the same gene, the 1298(A-->C) mutation, which changes a glutamate into an alanine residue. This mutation destroys an MboII recognition site and has an allele frequency of .33. This 1298(A-->C) mutation results in decreased MTHFR activity (one-way analysis of variance [ANOVA] P < .0001), which is more pronounced in the homozygous than heterozygous state. Neither the homozygous nor the heterozygous state is associated with higher plasma homocysteine (Hcy) or a lower plasma folate concentration-phenomena that are evident with homozygosity for the 677(C-->T) mutation. However, there appears to be an interaction between these two common mutations. When compared with heterozygosity for either the 677(C-->T) or 1298(A-->C) mutations, the combined heterozygosity for the 1298(A-->C) and 677(C-->T) mutations was associated with reduced MTHFR specific activity (ANOVA P < .0001), higher Hcy, and decreased plasma folate levels (ANOVA P <.03). Thus, combined heterozygosity for both MTHFR mutations results in similar features as observed in homozygotes for the 677(C-->T) mutation. This combined heterozygosity was observed in 28% (n =86) of the NTD patients compared with 20% (n =403) among controls, resulting in an odds ratio of 2.04 (95% confidence interval: .9-4.7). These data suggest that the combined heterozygosity for the two MTHFR common mutations accounts for a proportion of folate-related NTDs, which is not explained by homozygosity for the 677(C-->T) mutation, and can be an additional genetic risk factor for NTDs.

van der Put, N M; Gabreels, F; Stevens, E M; Smeitink, J A; Trijbels, F J; Eskes, T K; van den Heuvel, L P; Blom, H J

1998-01-01

85

Population distribution of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C risk alleles for methotrexate toxicity in Israel.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) is a central regulatory enzyme in the folate pathway. Two non-synonymous single nucleotide polymorphisms in MTHFR, C677T (rs1801133) and A1298C (rs1801131) have been associated with reduced MTHFR enzyme activity. These polymorphisms, especially C677T, appear to be linked with methotrexate-related toxicity, particularly hepatotoxicity; thus, pretreatment identification of individuals carrying these polymorphisms may be of clinical relevance. The purpose of this study was to determine the frequency and distribution of MTHFR polymorphic variants, known to functionally impair MTHFR activity, in the highly heterogeneous Israeli population. MTHFR genotyping was carried out in the representatives of three major demographic groups in Israel by PCR-restriction fragment length polymorphism and high-resolution melting. The relative distribution of variant alleles 677T and 1298C was found to be similar in individuals of Jewish, Druze and Arab Moslem descent (p = 0.09). However, Ashkenazi Jews displayed a 1.9-fold higher frequency of variant 677T and a 1.8-fold lower frequency of variant 1298C compared to non-Ashkenazi Jews (p < 0.001). Distinct differences in the relative frequencies of both polymorphisms were also found between Ashkenazi Jews and Druze (p < 0.01 for C677T, p < 0.01 for A1298C) or Ashkenazi Jews and Arab Moslem (p < 0.01 for C677T, p < 0.05 for A1298C). These data underscore the importance of geographic genetic analysis for a better understanding of human pharmacotherapy and personalized medicine. PMID:22847291

Efrati, Edna; Elkin, Hela; Nahum, Sagi; Krivoy, Norberto

2012-07-31

86

Impact of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on methotrexate-induced toxicities in acute lymphoblastic leukemia: a meta-analysis.  

PubMed

The associations between methylenetetrahydrofolate reductase (MTHFR) polymorphism and methotrexate (MTX)-induced toxicities in patients with acute lymphoblastic leukemia (ALL) have been evaluated in various populations, with the results remained conflicting. Therefore, we conducted a meta-analysis by combining available data to derive a more precise estimation of the association. PubMed, Embase, and China National Knowledge Infrastructure were searched until 21 September 2011 to identify eligible studies. A total of 14 studies were included, with all studies investigating MTHFR C677T polymorphism while nine of them investigating MTHFR A1298C polymorphism only. Results suggested that MTHFR C677T polymorphism was associated with significantly increased risk of MTX-induced toxicity, specifically liver toxicity (TT/CT vs. CC: odds ratio (OR) = 1.70, 95 % confidence interval (CI) = 1.05-2.75), myelosuppression (TT vs. CT/CC: OR = 2.82, 95 %CI = 1.25-6.34), oral mucositis (TT/CT vs. CC: OR = 3.68, 95 %CI = 1.73-7.85), gastrointestinal toxicity (TT/CT vs. CC: OR = 2.36, 95 %CI = 1.36-4.11), and skin toxicity (T vs. C: OR = 2.26, 95 %CI = 1.07-4.74). MTHFR A1298C polymorphism was found to be associated with decreased risk of skin toxicity (CC/AC vs. AA: OR = 0.11, 95 %CI = 0.01-0.85). Genotyping of MTHFR polymorphism, C677T particularly, prior to treatment for ALL is likely to be useful with the aim of tailoring MTX therapy and thus reducing the MTX-related toxicities. However, further studies with larger data set and well-designed models are required to validate our findings. PMID:22528943

Yang, Lin; Hu, Xin; Xu, Luhang

2012-04-20

87

General anesthesia and methylenetetrahydrofolate reductase deficiency.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) deficiency is an autosomal recessive disorder with a spectrum of manifestations including neurological symptoms, premature arteriosclerosis, and venous and arterial thrombosis. Most patients are heterozygous for multiple MTHFR substitutions; small minorities are homozygous for mutations at this locus. Among these mutations, the C677T polymorphism is the most deleterious. Nitrous oxide use in anesthesia leads to significant increases in plasma homocysteine. We present a patient undergoing urgent surgery with a preoperative diagnosis of homozygous MTHFR deficiency. PMID:18008117

Shay, Hamilton; Frumento, Robert J; Bastien, Alexandra

2007-11-01

88

Cerebral venous sinus thrombosis presenting as transient ischemic attacks in a case with homozygous mutations of MTHFR A1298C and CG677T.  

PubMed

We report a case with recurrent, transient attacks of slurred speech, weakness, and numbness of the right half of the face and the right arm without seizure activity, accompanied by headache and double vision. Neurologic examination revealed bilateral papilledema and right abducens palsy. Brain magnetic resonance imaging revealed thrombosis of the dural venous sinuses and the cortical veins, with no evidence of parenchymal lesion. Homozygous mutations were found for methylenetetrahydrofolate reductase (MTHFR) A1298C and MTHFR CG677T. Anticoagulation with heparin and warfarin resulted in prompt cessation of the transient attacks, as well as the signs and symptoms of increased intracranial pressure. This report documents that, although rare, transient ischemic attacks can result from cerebral venous thrombosis. PMID:20833086

Yildiz, Ozlem Kayim; Cevik, Seyda; Cil, Gulsum; Oztoprak, Ibrahim; Bolayir, Ertugrul; Topaktas, Suat

2010-09-15

89

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

Microsoft Academic Search

Objectives  Methylenetetrahydrofolate reductase (MTHFR), which is expressed in the liver, may be involved in both DNA methylation and\\u000a DNA synthesis. It is also indicated as a potential risk factor of liver cancer in patients with chronic liver disease. To\\u000a date, no study has been conducted on MTHFR and hepatocellular carcinoma (HCC) using a population-based design. The objective\\u000a of this study was

Li-Na Mu; Wei Cao; Zuo-Feng Zhang; Lin Cai; Qing-Wu Jiang; Nai-Chieh You; Binh Yang Goldstein; Guo-Rong Wei; Chuan-Wei Chen; Qing-Yi Lu; Xue-Fu Zhou; Bao-Guo Ding; Jun Chang; Shun-Zhang Yu

2007-01-01

90

Methylenetetrahydrofolate Reductase Polymorphisms Increase Risk of Esophageal Squamous Cell Carcinoma in a Chinese Population1  

Microsoft Academic Search

Methylenetetrahydrofolate reductase (MTHFR) plays a central role in folate metabolism that affects DNA methylation and synthesis. Because germ-line mutations at nucleotides 677 (C3 T) and 1298 (A3 C) in the MTHFR gene cause diminished enzyme activity, and aberrant DNA meth- ylation is oncogenic, we examined the relationship between these two MTHFR polymorphisms and susceptibility to esophageal squamous cell carcinoma (ESCC)

Chunying Song; Deyin Xing; Wen Tan; Qingyi Wei; Dongxin Lin

2001-01-01

91

An MTHFR variant, homocysteine, and cardiovascular comorbidity in renal disease  

Microsoft Academic Search

An MTHFR variant, homocysteine, and cardiovascular comorbidity in renal disease.BackgroundIt is unclear whether total serum homocysteine (tHcy) and the C677T mutation of methylenetetrahydrofolate reductase (MTHFR) are associated with cardiovascular disease (CVD) in patients with end-stage renal disease (ESRD).MethodsA cross-sectional sample of 459 patients with ESRD on chronic dialysis was assessed to determine whether tHcy and the C677T mutation are associated

Elizabeth M. Wrone; James L. Zehnder; John M. Hornberger; Linda M. McCann; Norman S. Coplon; Stephen P. Fortmann

2001-01-01

92

The thermolabile variant 677C-->T can further reduce activity when expressed in cis with severe mutations for human methylenetetrahydrofolate reductase.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) catalyses the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a carbon donor for homocysteine remethylation to methionine. Severe MTHFR deficiency is associated with hyperhomocysteinemia and homocystinuria. These patients show a wide variety of neurological and vascular symptoms, with variable age of onset. Residual enzyme activity is usually less than 20% of control values, and correlates reasonably well with age of onset of symptoms. A milder deficiency of MTHFR, with 30%-50% residual enzyme activity and increased enzyme thermolability, has been described as a risk factor for vascular disease and for neural tube defects. In earlier work, we isolated the human cDNA for MTHFR, and reported 14 mutations in severe MTHFR deficiency, as well as a common 677C-->T missense mutation (Ala-->Val) that encodes the thermolabile MTHFR. This variant has also been observed in some patients with severe MTHFR deficiency, in cis with their severe mutations. We report here the in vitro expression of seven severe MTHFR mutations in a bacterial expression system; six of these were expressed in cis with the Val allele to mimic the situation in the patients. We show that three of these constructs have significantly reduced enzyme activity (<10% of control); the presence of the thermolabile variant in these patients in cis is unlikely to affect enzyme function since activity is already low. One mutation causes a dramatic increase in activity when it is expressed in cis with the Ala allele, but is associated with extreme lability when in cis with the Val allele. Three mutations cause moderate decreases in enzyme activity, with a further decrease in activity when they are in cis with the Val allele. We hypothesize that deleterious mutations which alter stability may be compromised to a greater degree when the thermolabile variant is present on the same allele. PMID:10923034

Goyette, P; Rozen, R

2000-01-01

93

MTHFR polymorphisms in gastric cancer and in first-degree relatives of patients with gastric cancer  

Microsoft Academic Search

Two common mutations, 677 C?T and a1298 A?C, in the methylenetetrahydrofolate reductase gene (MTHFR) reduce the activity of\\u000a MTHFR and folate metabolism. Familial aggregation in a variable but significant proportion of gastric cancer (GC) cases suggests\\u000a the importance of genetic predisposition in determining risk. In this study, we evaluate MTHFR polymorphisms in 57 patients\\u000a with a diagnosis of GC, in

Valli De Re; R. Cannizzaro; V. Canzonieri; E. Cecchin; L. Caggiari; E. De Mattia; C. Pratesi; P. De Paoli; G. Toffoli

2010-01-01

94

Molecular Analysis of Factor V Leiden, Factor V Hong Kong, Factor II G20210A, Methylenetetrahydrofolate Reductase C677T, and A1298C Mutations Related to Turkish Thrombosis Patients  

Microsoft Academic Search

Inherited gene disorders related to the hemostatic system have been documented as risk factors for thrombosis. The roles of factor V Hong Kong (FV Hong Kong), factor V Leiden (FV Leiden), factor II G20210A (FII G20210A), methylenetetrahydrofolate reductase (MTHFR) C677T, and MTHFR A1298C mutations in Turkish patients with thrombosis (270 patients) compared with healthy controls (114 subjects) were evaluated. Polymerase

Bilgen Dölek; Serpil Eraslan; Sevim Ero?lu; Belgin Eroglu Kesim; Turgut Ulutin; Altan Yalç?ner; Yahya R. Laleli; Nermin Gözükirm?z?

2007-01-01

95

Influence of Combined Methionine Synthase (MTR 2756A > G) and Methylenetetrahydrofolate Reductase (MTHFR 677C > T) Polymorphisms to Plasma Homocysteine Levels in Korean Patients with Ischemic Stroke  

PubMed Central

Purpose Methionine synthase (MTR) and 5,10-methylenetetrahydrofolate reductase (MTHFR) are the main regulatory enzymes for homocysteine metabolism. The present case-control study was conducted to determine whether there is an association between the MTR 2756A > G or MTHFR 677C > T polymorphism and plasma homocysteine concentration in Korean subjects with ischemic stroke. Materials and Methods DNA samples of 237 patients who had an ischemic stroke and 223 age and sex-matched controls were studied. MTR 2756A > G and MTHFR 677C > T genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results Frequencies of mutant alleles for MTR and MTHFR polymorphisms were not significantly different between the controls and cases. The patient group, however, had significantly higher homocysteine concentrations of the MTR 2756AA and MTHFR 677TT genotypes than the control group (p = 0.04 for MTR, p = 0.01 for MTHFR). The combined MTR 2756AA and MTHFR 677TT genotype (p = 0.04) and the homocysteine concentrations of the patient group were also higher than those of the controls. In addition, the genotype distribution was significant in the MTHFR 677TT genotype (p = 0.008) and combined MTR 2756AA and MTHFR 677TT genotype (p = 0.03), which divided the groups into the top 20% and bottom 20% based on their homocysteine levels. Conclusion The results of the present study demonstrate that the MTR 2756A > G and MTHFR 677C > T polymorphisms interact with elevated total homocysteine (tHcy) levels, leading to an increased risk of ischemic stroke.

Kim, Ok Joon; Hong, Sun Pyo; Ahn, Jung Yong; Hong, Seung Ho; Hwang, Tae Sun; Kim, Soo Ok; Yoo, Wangdon; Oh, Doyeun

2007-01-01

96

Molecular genetic analysis in mild hyperhomocysteinemia : a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease  

Microsoft Academic Search

Mild hyperhomocysteinemia is an established risk factor for cardiovascular disease. Genetic aberrations in the cystathionine P-synthase (CBS) and methylenetetrahydrofolate reductase (MTHFR) genes may account for reduced enzyme activities and elevated plasma homocysteine levels. In 15 unrelated Dutch patients with homozygous CBS deficiency, we observed the 833TâC (1278T) mutation in 50% of the alleles. Very recently, we identified a common mutation

L. A. J. Kluijtmans; L. P. W. J. van den Heuvel; G. H. J. Boers; P. Frosst; E. M. B. Stevens; B. A. van Oost; M. den Heijer; J. M. F. Trijbels; R. Rozen; H. J. Blom

1996-01-01

97

Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism and Age at Onset of Schizophrenia: No Consistent Evidence for an Association in the Nordic Population  

PubMed Central

Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in metabolic pathways of importance for nucleotide synthesis and methylation of DNA, membranes, proteins and lipids. The MTHFR gene includes a common polymorphism (rs1801133 or C677T), which is associated with enzyme activity. The T-allele of the C677T polymorphism has been associated with earlier age at onset of schizophrenia in a Scandinavian population, although no association was found in replication attempts in other populations. Extending the study to five Nordic samples consisting of 2,198 patients with schizophrenia, including the original Scandinavian samples, there was no significant association between MTHFR C677T polymorphism and age at onset in schizophrenia. The present results do not suggest that the investigated MTHFR polymorphism has any significant influence on age at onset of schizophrenia in the Nordic population. © 2012 Wiley Periodicals, Inc.

Saetre, Peter; Grove, Jakob; B?rglum, Anders D; Mors, Ole; Werge, Thomas; Andreassen, Ole A; Vares, Maria; Agartz, Ingrid; Terenius, Lars; Jonsson, Erik G

2012-01-01

98

Methylene tetrahydrofolate reductase (MTHFR) and nitric oxide synthase (ecNOS) genes and risks of peripheral arterial disease and coronary heart disease: Edinburgh artery study  

Microsoft Academic Search

Hyperhomocysteinaemia and reduced nitric oxide synthesis may each result in endothelial dysfunction predisposing to atherogenesis. Genetic variants of methylene tetrahydrofolate reductase (MTHFR) and endothelial nitric oxide synthase (ecNOS) influence homocysteine metabolism and nitric oxide synthesis, respectively and might thus be determinants of the risk of atherosclerotic disease. The aim of our study was to identify, in a general population sample,

F. G. R Fowkes; A. J Lee; C. M Hau; A Cooke; J. M Connor; G. D. O Lowe

2000-01-01

99

C677T (thermolabile alanine\\/valine) polymorphism in methylenetetrahydrofolate reductase (MTHFR): its frequency and impact on plasma homocysteine concentration in different European populations  

Microsoft Academic Search

A common polymorphism has been described in the methylenetetrahydrofolate reductase (MTHFR) gene, substituting an alanine (A) for a valine (V), where the V allele results in a thermolabile enzyme with reduced activity. This polymorphism is easily detectable by PCR amplification and digestion with HinfI restriction enzyme. We describe the use of the MADGE high throughput genotyping system for rapid typing

Vilmundur Gudnason; David Stansbie; Jeff Scott; Ann Bowron; Viviane Nicaud; Steve Humphries

1998-01-01

100

Study of MTHFR and MS polymorphisms as risk factors for NTD in the Italian population  

Microsoft Academic Search

Homozygosity for the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is a risk factor for neural tube defects (NTDs) in many populations, including Italians. Another common mutation on\\u000a the MTHFR gene, A1298C, has also been described as a risk mutation. Furthermore, several studies have suggested that a defective methionine\\u000a synthase (MS) enzyme could be a critical defect in folate-related

Patrizia De Marco; Maria Grazia Calevo; Anna Moroni; Lorenza Arata; Elisa Merello; Richard H. Finnell; Huiping Zhu; Luciano Andreussi; Armando Cama; Valeria Capra

2002-01-01

101

Two cousins with neonatal stroke, PAI-1 4G variant and MTHFR A1298C mutation.  

PubMed

The authors describe 2 female cousins with neonatal stroke. One was heterozygous for the plasminogen activator inhibitor-1 4G variant and compound heterozygous for the A1298C and C677T methylenetetrahydrofolate reductase mutations. Her cousin was homozygous for the plasminogen activator inhibitor-1 4G variant and heterozygous for the methylenetetrahydrofolate reductase A1298C and factor V Leiden mutations. PMID:17641264

Golomb, Meredith R; Heiny, Mark; Garg, Bhuwan P

2007-06-01

102

Methylenetetrahydrofolate reductase (MTHFR) polymorphism A1298C (Glu429Ala) predicts decline in renal function over time in the African-American Study of Kidney Disease and Hypertension (AASK) Trial and Veterans Affairs Hypertension Cohort (VAHC)  

PubMed Central

Background. Hyperhomocysteinemia is associated with increased venous thrombosis and cardiovascular disease (CVD). Mutations in the human methylenetetrahydrofolate reductase (MTHFR) gene have been associated with increased homocysteine levels and risks of CVD in various populations including those with kidney disease. Here, we evaluated the influence of MTHFR variants on progressive loss of kidney function. Methods. We analyzed 821 subjects with hypertensive nephrosclerosis from the longitudinal National Institute of Diabetes and Digestive and Kidney Diseases African-American Study of Kidney Disease and Hypertension (AASK) Trial to determine whether decline in glomerular filtration rate (GFR) over ?4.2 years was predicted by common genetic variation within MTHFR at non-synonymous positions C677T (Ala222Val) and A1298C (Glu429Ala) or by MTHFR haplotypes. The effect on GFR decline was then supported by a study of 1333 subjects from the San Diego Veterans Affairs Hypertension Cohort (VAHC), followed over ?4.5 years. Linear effect models were utilized to determine both genotype [single-nucleotide polymorphism (SNP)] and genotype (SNP)-by-time interactions. Results. In AASK, the polymorphism at A1298C predicted the rate of GFR decline: A1298/A1298 major allele homozygosity resulted in a less pronounced decline of GFR, with a significant SNP-by-time interaction. An independent follow-up study in the San Diego VAHC subjects supports that A1298/A1298 homozygotes have the greatest estimated GFR throughout the study. Haplotype analysis with C677T yielded concurring results. Conclusion. We conclude that the MTHFR-coding polymorphism at A1298C is associated with renal decline in African-Americans with hypertensive nephrosclerosis and is supported by a veteran cohort with a primary care diagnosis of hypertension. Further investigation is needed to confirm such findings and to determine what molecular mechanism may contribute to this association.

Salem, Rany M.; Lipkowitz, Michael S.; Bhatnagar, Vibha; Pandey, Braj; Schork, Nicholas J.; O'Connor, Daniel T.

2012-01-01

103

A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells  

PubMed Central

A common mutation (C677T) in the gene encoding for methylenetetrahydrofolate reductase (MTHFR) (5-methyltetrahydrofolate:(acceptor) oxidoreductase, EC 1.7.99.5), a key regulatory enzyme in one-carbon metabolism, results in a thermolabile variant of the MTHFR enzyme with reduced activity in vitro. In the present study we used a chromatographic method for folate analysis to test the hypothesis that this mutation would be associated with altered distribution of red blood cell (RBC) folates. An alteration was found as manifested by the presence of formylated tetrahydrofolate polyglutamates in addition to methylated derivatives in the RBCs from homozygous mutant individuals. 5-Methyltetrahydrofolate polyglutamates were the only folate form found in RBCs from individuals with the wild-type genotype. Existence of formylated folates in RBCs only from individuals with the thermolabile MTHFR is consistent with the hypothesis that there is in vivo impairment in the activity of the thermolabile variant of MTHFR and that this impairment results in an altered distribution of RBC folates.

Bagley, Pamela J.; Selhub, Jacob

1998-01-01

104

Impact of new mutations in the methylenetetrahydrofolate reductase gene assessed on biochemical phenotypes: a familial study.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) deficiency was identified in two out of four children born from nonconsanguineous parents. One of the affected children exhibited some clinical findings suggesting cystathionine beta-synthase deficiency; MTHFR activity was extremely reduced. In addition, hyperhomocysteinaemia, hypomethioninaemia, low total folate, especially methylfolate in red blood cells, and a reduced methylfolate/total folate ratio were found. Two mutations not yet reported, one on exon 1 of the gene changing an arginine to stop codon and one other on exon 9 changing an arginine to tryptophan were identified in both children in the compound heterozygous state associated with a common polymorphism, 1298A>C, also in the heterozygous state. The mother, homozygous for the mutation on exon 9 and for the polymorphism 1298A>C on exon 7, was clinically and biochemically normal, with normal folate status, mainly methylfolate levels in red blood cells, although MTHFR activity was moderately decreased. The father, heterozygous for the transition arginine to stop codon and for the common polymorphism 677C>T on exon 4, exhibited major biochemical abnormalities, hyperhomocysteinaemia and low methylfolate levels in red blood cells, but was clinically normal. The unaffected children had a biochemical pattern close to that of their mother and were heterozygous for the mutation on exon 9 and also for the two common polymorphisms, 677C>T and 1298A>C. In the affected children, some biochemical abnormalities, including folate status, especially methylfolate levels, were improved with treatment combining methyltetrahydrofolic acid, hydroxocobalamin, pyridoxine and betaine; however, homocysteine concentrations remained high and methionine concentrations were lowered. The father was treated with folic acid, which partially improved biochemical abnormalities. The impact of these mutations is discussed. PMID:11916316

Tonetti, C; Amiel, J; Munnich, A; Zittoun, J

2001-12-01

105

Association of Methylenetetrahydrofolate Reductase (MTHFR 677C>T and 1298A>C) Polymorphisms and Haplotypes with Silent Brain Infarction and Homocysteine Levels in a Korean Population  

PubMed Central

Purpose Methylenetetrahydrofolate reductase (MTHFR) is the main regulatory enzyme for homocysteine metabolism. In the present study, we evaluated whether the MTHFR 677C>T and 1298A>C gene polymorphisms are associated with SBI and plasma homocysteine concentration in a Korean population. Materials and Methods We enrolled 264 patients with SBI and 234 healthy controls in South Korea. Fasting plasma total homocysteine (tHcy) concentrations were measured, and genotype analysis of the MTHFR gene was carried out. Results The plasma tHcy levels were significantly higher in patients with SBI than in healthy controls. Despite a significant association between the MTHFR 677TT genotype and hyperhomocysteinemia, the MTHFR 677C>T genotypes did not appear to influence susceptibility to SBI. However, odds ratios of the 1298AC and 1298AC + CC genotypes for the 1298AA genotype were significantly different between SBI patients and normal controls. The frequencies of 677C-1298A and 677C-1298C haplotypes were significantly higher in the SBI group than in the control group. Conclusion This study demonstrates that the MTHFR 1298A>C polymorphism is a risk factor for SBI in a Korean population. The genotypes of 677C>T and 1298A>C polymorphisms interact additively, and increase the risk of SBI in Korean subjects.

Han, In Bo; Kim, Ok Joon; Ahn, Jung Yong; Oh, Doyeun; Hong, Sun Pyo; Huh, Ryoong; Chung, Sang Sup

2010-01-01

106

Plasma folate, methylenetetrahydrofolate reductase (MTHFR), and colorectal cancer risk in three large nested case-control studies.  

PubMed

Few prospective studies have examined the associations between blood levels of folate, in conjunction with methylenetetrahydrofolate reductase (MTHFR) polymorphisms, and colorectal cancer. We evaluated the associations between plasma folate, MTHFR C677T, and A1298C, and colorectal cancer in three large prospective studies: the Nurses' Health Study, the Health Professionals Follow-up Study, and the Physicians' Health Study. A total of 602 incident cases were identified and individually matched to controls who provided blood specimens. We used conditional logistic regression to calculate the relative risk (RR) and 95% confidence interval (95% CI) and then pooled the estimates using a random effects model. We found a lower risk of colorectal cancer among participants with low plasma folate levels: compared with the lowest quartile, RRs (95% CIs) for each successively higher quartile of plasma folate levels were 1.55 (1.14-2.11), 1.37 (1.00-1.88), and 1.47 (1.07-2.01; P for trend = 0.10). For the MTHFR polymorphisms, RRs (95% CIs) were 0.62 (0.44-0.90) for 677TT versus CC/CT and 0.68 (0.31-1.51) for 1298CC versus AC/AA, and these lower-risk genotypes were associated with lower circulating plasma folate levels. When we partitioned the variation in plasma folate levels, variation due to folate intake was not positively associated with colorectal cancer risk. We found that low plasma folate levels were associated with lower risk of colorectal cancer. The reasons underlying a lower risk of colorectal cancer with low plasma folate levels require elucidation because plasma folate levels can reflect dietary intake, genetic influences, and other factors. PMID:22367721

Lee, Jung Eun; Wei, Esther K; Fuchs, Charles S; Hunter, David J; Lee, I-Min; Selhub, Jacob; Stampfer, Meir J; Willett, Walter C; Ma, Jing; Giovannucci, Edward

2012-02-26

107

[Molecular genetics of MTHFR: polymorphisms are not all benign].  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) is a key regulatory enzyme in folate and homocysteine metabolism. Research performed during the past decade has clarified our understanding of MTHFR deficiencies that cause homocystinuria or mild hyperhomocysteinemia. Our cloning of the MTHFR coding sequence was initially followed by the identification of the first deleterious mutations in MTHFR, in patients with homocystinuria and marked hyperhomocysteinemia. Shortly thereafter, we identified the 677C-->T variant and showed that it encoded a thermolabile enzyme with reduced activity. Currently, a total of 41 rare but deleterious mutations in MTHFR, as well as about 60 polymorphisms have been reported. The 677C-->T (Ala222Val) variant has been particularly noteworthy since it has become recognized as the most common genetic cause of hyperhomocysteinemia. The disruption of homocysteine metabolism by this polymorphism influences risk for several complex disorders, including cardiovascular disease, neural tube defects and some cancers. We describe here the complex structure of the MTHFR gene, summarize the current state of knowledge on rare and common mutations in MTHFR and discuss some relevant findings in a mouse model for MTHFR deficiency. PMID:17349292

Leclerc, Daniel; Rozen, Rima

2007-03-01

108

Methylenetetrahydrofolate Reductase C677T and A1298C Mutations in Women with Recurrent Spontaneous Abortions in the Northwest of Iran  

PubMed Central

Introduction. Recurrent spontaneous abortion (RSA) is a significant obstetrical complication that may occur during pregnancy. Various studies in recent years have indicated that two common mutations (C677T and A1298C) of the methylenetetrahydrofolate reductase (MTHFR) gene are risk factor for RSA. This study was carried out to determine the influence of (C677T and A1298C) of the methylenetetrahydrofolate reductase (MTHFR) gene mutations with RSA. Materials and Methods. A total of 139 women were included in this study: 89 women with two or more consecutive miscarriages and 50 healthy controls. Total genomic DNA was isolated from blood leukocytes. To determine the frequency of the two common C677T and A1298C MTHFR gene mutations in the patients and controls, we used two methods, amplification refractory mutation system-PCR and PCR-restriction fragment length polymorphism. Results. There is no significant difference in the prevalence of 677T/T genotype among women with RSA and healthy controls (P = 0.285). Also no statistically significant difference in the frequency of A1298C MTHFR gene mutation was detected between the two groups (P = 0.175 ). Conclusion. In conclusion, the results indicate that the Amplification Refractory Mutation System-PCR method was in complete concordance with the results obtained by standard PCR-restriction fragment length polymorphism method. The results also show no significant difference in MTHFR C677T/A1298C genotype distribution among the two groups; therefore, further studies on larger population and other genetic variants to better understand the pathobiology of RSA are needed.

Poursadegh Zonouzi, Ahmad; Chaparzadeh, Nader; Asghari Estiar, Mehrdad; Mehrzad Sadaghiani, Mahzad; Farzadi, Laya; Ghasemzadeh, Alieh; Sakhinia, Masoud; Sakhinia, Ebrahim

2012-01-01

109

Mutations C677T and A1298C of the 5,10-methylenetetrahydrofolate reductase gene and fasting plasma homocysteine levels are not associated with the increased risk of venous thromboembolic disease.  

PubMed

Mild hyperhomocysteinemia is associated with homozygosity for the thermolabile variant of 5,10-methylenetetrahydrofolate reductase (MTHFR) and could increase the risk of venous thromboembolic disease (VTD). Recently, the second A1298C mutation of the MTHFR gene was described. The present study aimed to analyze both mutations of the MTHFR gene and plasma homocysteine levels in subjects with VTD. The study groups comprised 146 patients with VTD and 100 healthy subjects. There were no statistical differences in carrier frequency and allelic frequency for both A1298C and C677T mutations, nor were there any differences encountered between subjects with VTD and controls in either plasma homocysteine levels or according to C677T or A1298C genotypes of MTHFR. In our VTD patients and controls, neither MTHFR 677CT/1298CC nor MTHFR 677TT/1298CC combined genotypes were observed; double heterozygotes (A1298C/C677T) were represented only in 11% of VTD patients, and in 15% of the controls. In conclusion, the polymorphisms C677T and A1298C of MTHFR and fasting plasma homocysteine levels do not seem to be significant risk factors for venous thromboembolic disease. PMID:12138370

Domagala, T B; Adamek, L; Nizankowska, E; Sanak, M; Szczeklik, A

2002-07-01

110

Hyperhomocysteinemia increases the risk of venous thrombosis independent of the C677T mutation of the methylenetetrahydrofolate reductase gene in selected Brazilian patients  

Microsoft Academic Search

Fasting total homocysteine (tHcy) and the methylenetetrahydrofolate reductase (MTHFR) C677T mutation were evaluated in 91 patients with venous thromboembolism and without acquired thrombophilia, and in 91 age-matched and sex-matched controls. Hyperhomocysteinemia was detected in 11 patients (12.1%) and in two controls (2.2%), yielding an odds ratio (OR) for venous thrombosis of 6.1 (95% confidence interval (CI), 1.3-28.4). After excluding 21

V. M. Morelli; D. M. Lourenco; V. D'Almeida; R. F. Franco; F. Miranda; M. A. Zago; M. A. E. Noguti; E. Cruz; J. Kerbauy

111

Increased frequency of combined methylenetetrahydrofolate reductase C677T and A1298C mutated alleles in spontaneously aborted embryos.  

PubMed

The pathogenesis of spontaneous abortion is complex, presumably involving the interaction of several genetic and environmental factors. The methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms are commonly associated with defects in folate dependent homocysteine metabolism and have been implicated as risk factors for recurrent embryo loss in early pregnancy. In the present study we have determined the prevalence of combined MTHFR C677T and A1298C polymorphisms in DNA samples from spontaneously aborted embryos (foetal death between sixth and twentieth week after conception) and adult controls using solid-phase minisequencing technique. There was a significant odds ratio of 14.2 (95% CI 1.78-113) in spontaneously aborted embryos comparing the prevalence of one or more 677T and 1298C alleles vs the wild type combined genotype (677CC/1298AA), indicating that the MTHFR polymorphisms may have a major impact on foetal survival. Combined 677CT/1298CC, 677TT/1298AC or 677TT/1298CC genotypes, which contain three or four mutant alleles, were not detected in any of the groups, suggesting complete linkage disequilibrium between the two polymorphisms. The present finding of high prevalence of mutated MTHFR genotypes in spontaneously aborted embryos emphasises the potential protective role of periconceptional folic acid supplementation. PMID:11938441

Zetterberg, Henrik; Regland, Björn; Palmér, Mona; Ricksten, Anne; Palmqvist, Lars; Rymo, Lars; Arvanitis, Demetrios A; Spandidos, Demetrios A; Blennow, Kaj

2002-02-01

112

Association of methylenetetrahydrofolate reductase (MTHFR) polymorphisms with genetic susceptibility to gastric cancer: a meta-analysis  

Microsoft Academic Search

To clarify the influence of MTHFR C677T and A1298C polymorphisms on gastric cancer (GC), a meta-analysis of eight case-control studies (1,584\\/2,785 cases\\/controls) was carried out. Overall, there was moderate heterogeneity among studies, and the C677T allele T was associated with a 27% increased risk of GC compared with C allele: the random effects (RE) OR (95% confidence interval in parenthesis)

Elias Zintzaras

2006-01-01

113

Pediatric stroke and methylenetetrahydrofolate reductase polymorphisms: an examination of C677T and A1298C mutations.  

PubMed

Although rare in children, stroke is becoming increasingly recognized as an important cause of morbidity and mortality with an annual incidence of approximately 3 per 100,000 per year. While several studies have documented the underlying mechanisms and pathogenesis related to stroke in adults, including genetic and acquired prothrombotic conditions, the data available on similar conditions in children is limited. Evidence suggests that mutations in methylenetetrahydrofolate reductase (MTHFR) appear to be linked with hyperhomocysteinemia (HHC) and cerebral-thrombotic events in children. While the C677T common missense mutation is the best-characterized MTHFR polymorphism, another common missense mutation, A1298C also exists. A recent study of children demonstrated that the homozygous form of C677T polymorphism occurred two-times as often in those with stroke versus healthy controls. In our retrospective chart review of 33 children seen at Children's Hospital of Orange County from January 1, 2000 to September 30, 2003 with the diagnosis of stroke, we examined both the C677T and A1298C polymorphisms for occurrence and type. In the subset (n=21), which excluded those with a confounding disorder, we observed a significant increase in the frequency of A1298C and C677T homozygosity (0.25 [p=0.01] and 0.20 [p=0.100], respectively); expected rate: (0.06 and 0.08, respectively). Our observed rates of heterozygosity for both MTHFR mutations (0.35 and 0.40, respectively) were consistent with expected rates (0.28 and 0.38, respectively). In all subjects, homocysteine (HC) levels were normal. The results of our study suggest that mutations in MTHFR are associated with pediatric stroke. However, additional studies are required to confirm our findings and to determine if this relationship is causal. PMID:16282888

Rook, James L; Nugent, Diane J; Young, Guy

2005-11-01

114

Malignant stroke in an adolescent with a homozygous MTHFR 677CT mutation and intake of hormonal contraceptives.  

PubMed

Severe stroke in children and adolescents with its devastating long term consequences remains a rare disorder with many open questions. Beside the well known risk factors such as infection or congenital and acquired heart disease, coagulation disorders have to be considered in the differential work up of the underlying aetiology. Here we report the case of an adolescent with a homozygote MTHFR 677CT mutation suffering a malignant stroke shortly after the start of oral contraceptives. Conclusion: Since prevention seems easily feasible, general screening for MTHFR mutations might be worthwhile in women before starting oral contraceptives. PMID:19763346

Pfurtscheller, K; Senning, B; Bernhard, H; Novak, M; Zobel, G; Plecko, B; Muntean, W

2009-10-01

115

Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and susceptibility to diabetic nephropathy in Chinese type 2 diabetic patients: a meta-analysis.  

PubMed

The association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and diabetic nephropathy (DN) or diabetes mellitus (DM) risk has been widely reported, but the results are still debatable. To investigate the role of MTHFR C677T polymorphism on DM or DN, 13 separate studies in the Chinese population on the relation between MTHFR C677T polymorphism and DM or DN were analyzed by a meta-analysis. Five genetic models were used to estimate the association between MTHFR C677T polymorphism and the risk of DM or DN. Overall, our meta-analysis for DN versus healthy controls produced significant results for all genetic contrasts except for the co-dominant model (allele contrast: OR?=?2.24, 95%CI: 1.88-2.65, p?MTHFR C677T polymorphism might influence DN risk, but not for DM in the Chinese population. PMID:23822721

Chang, Wei-wei; Zhang, Liu; Yao, Ying-shui; Su, Hong; Jin, Yue-long; Chen, Yan

2013-07-03

116

Low frequency of mutated methylenetetrahydrofolate reductase 677C-->T and 1298A-->C genetics single nucleotide polymorphisms (SNPs) in Sub-Saharan populations.  

PubMed

5,10-Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) are two of the key enzymes in the folate/vitamin B12-dependent remethylation of homocysteine to methionine. The frequencies of MTHFR single nucleotide polymorphisms (SNPs), 677C-->T, 1298A-->C, 1317T-->C and of MTR, 2756A-->G, have been widely studied in Caucasians, but they have never been reported simultaneously in a large population from Sub-Saharan Africa. Presently, we report the prevalence of these SNPs and their relationship to homocysteine in 240 subjects recruited in West Africa. The frequencies of the mutant genotypes 677TT (0.8%) and 1298CC (2%) were lower than that usually observed in Caucasians, while the frequency of the mutant 1317CC was higher (16%). We formed a systematic association of the mutated MTHFR 677C-->T SNP with a 1298A/1317T common haplotype. The MTHFR mutant genotype 677TT was associated with an intermediate hyperhomocysteinemia (92.4 +/- 6.0 micromol/l) higher than that described in Caucasians. The 2756A-->G SNP in the MTR was similarly distributed in Africans compared to Caucasians. In conclusion, the MTHFR 677TTor 1298CC genotypes are much rarer in Africans than in Caucasians. The 677TT low frequency may be related to the high effect of this mutation on homocysteine metabolism in the environmental conditions of this African region. PMID:12964809

Adjalla, Charles E; Amouzou, Emile K; Sanni, Ambaliou; Abdelmouttaleb, Idrissia; Chabi, Nicodčme W; Namour, Fares; Soussou, Batoma; Guéant, Jean-Louis

2003-08-01

117

Molecular genetic analysis in mild hyperhomocysteinemia: A common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease  

SciTech Connect

Mild hyperhomocysteinemia is an established risk factor for cardiovascular disease. Genetic aberrations in the cystathionine P-synthase (CBS) and methylenetetrahydrofolate reductase (MTHFR) genes may account for reduced enzyme activities and elevated plasma homocysteine levels. In 15 unrelated Dutch patients with homozygous CBS deficiency, we observed the 833T{yields}C (1278T) mutation in 50% of the alleles. Very recently, we identified a common mutation (677C{yields}T; A{yields}V) in the MTHFR gene, which, in homozygous state, is responsible for the thermolabile phenotype and which is associated with decreased specific MTHFR activity and elevated homocysteine levels. We screened 60 cardiovascular patients and 111 controls for these two mutations, to determine whether these mutations are risk factors for premature cardiovascular disease. Heterozygosity for the 833T{yields}C mutation in the CBS gene was observed in one individual of the control group but was absent in patients with premature cardiovascular disease. Homozygosity for the 677C-{yields}T mutation in the MTHFR gene was found in 9 (15%) of 60 cardiovascular patients and in only 6 ({approximately}5%) of 111 control individuals (odds ratio 3.1 [95% confidence interval 1.0-9.21]). Because of both the high prevalence of the 833T-{yields}C mutation among homozygotes for CBS deficiency and its absence in 60 cardiovascular patients, we may conclude that heterozygosity for CBS deficiency does not appear to be involved in premature cardiovascular disease. However, a frequent homozygous mutation in the MTHFR gene is associated with a threefold increase in risk for premature cardiovascular disease. 35 refs., 3 figs., 1 tab.

Kluijtmans, L.A.J.; Heuvel, L.P.W.J. van den; Stevens, E.M.B. [Univ. Hospital Nijmegen (Netherlands)] [and others

1996-01-01

118

Effect of Riboflavin Status on the Homocysteine-lowering Effect of Folate in Relation to the MTHFR (C677T) Genotype  

Microsoft Academic Search

Background: Riboflavin (vitamin B2) is the precursor for FAD, the cofactor for methylenetetrahydrofolate reductase (MTHFR). MTHFR catalyzes the formation of 5-methyltetrahydrofolate, which acts as a methyl donor for homocysteine remethylation. Individuals with the MTHFR 677C3 T mutation have increased plasma total homocysteine (tHcy) concentrations, particularly in as- sociation with low folate status. It has been proposed that riboflavin may act

Stuart J. Moat; Pauline A. L. Ashfield-Watt; Hilary J. Powers; Robert G. Newcombe; Ian F. W. McDowell

2003-01-01

119

Combined portal, splenic and mesenteric venous thrombosis in inactive ulcerative colitis with heterozygous mutation in MTHFR gene: A rare case of thrombophilia  

PubMed Central

Thrombophilia is a rare but potentially catastrophic phenomenon occurring in patients having tendency of thrombosis. It may lead to serious complications. The etiology of thrombophilia is thought to be multifactorial and related to both acquired and inherited factors. Inflammatory bowel disease is an acquired cause of thrombophilia. Thromboembolic events are seen during inflammatory bowel disease, especially during the active period of the disease. In inflammatory bowel disease, thrombus formation in portal, splenic and mesenteric veins are not common. Besides, the association of genetic disorders related to metabolism of homocysteine with inflammatory bowel disease has been evidenced, especially in Crohn disease and rarely in ulcerative colitis. We present a rare case of ulcerative colitis in association with combined portal, splenic and mesenteric vein thrombosis. The patient was recently diagnosed with the disease which was in the inactive period. Interestingly, our patient was also heterozygous for the mutation in methylenetetrahydrofolate reductase (MTHFR) gene.

Gursoy, Gul; Cimbek, Ahmet; Acar, YaSar; Erol, Birsen; Dal, Hayriye Cankar; Evrin, Nuray; Gungor, Asl?

2011-01-01

120

Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study  

PubMed Central

Background: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. Methods: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. Results: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95%CI 1.10–2.04 and HR 2.16, 95%CI 1.24–3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. Conclusion: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.

Jakubowska, A; Rozkrut, D; Antoniou, A; Hamann, U; Scott, R J; McGuffog, L; Healy, S; Sinilnikova, O M; Rennert, G; Lejbkowicz, F; Flugelman, A; Andrulis, I L; Glendon, G; Ozcelik, H; Thomassen, M; Paligo, M; Aretini, P; Kantala, J; Aroer, B; von Wachenfeldt, A; Liljegren, A; Loman, N; Herbst, K; Kristoffersson, U; Rosenquist, R; Karlsson, P; Stenmark-Askmalm, M; Melin, B; Nathanson, K L; Domchek, S M; Byrski, T; Huzarski, T; Gronwald, J; Menkiszak, J; Cybulski, C; Serrano, P; Osorio, A; Cajal, T R; Tsitlaidou, M; Benitez, J; Gilbert, M; Rookus, M; Aalfs, C M; Kluijt, I; Boessenkool-Pape, J L; Meijers-Heijboer, H E J; Oosterwijk, J C; van Asperen, C J; Blok, M J; Nelen, M R; van den Ouweland, A M W; Seynaeve, C; van der Luijt, R B; Devilee, P; Easton, D F; Peock, S; Frost, D; Platte, R; Ellis, S D; Fineberg, E; Evans, D G; Lalloo, F; Eeles, R; Jacobs, C; Adlard, J; Davidson, R; Eccles, D; Cole, T; Cook, J; Godwin, A; Bove, B; Stoppa-Lyonnet, D; Caux-Moncoutier, V; Belotti, M; Tirapo, C; Mazoyer, S; Barjhoux, L; Boutry-Kryza, N; Pujol, P; Coupier, I; Peyrat, J-P; Vennin, P; Muller, D; Fricker, J-P; Venat-Bouvet, L; Johannsson, O Th; Isaacs, C; Schmutzler, R; Wappenschmidt, B; Meindl, A; Arnold, N; Varon-Mateeva, R; Niederacher, D; Sutter, C; Deissler, H; Preisler-Adams, S; Simard, J; Soucy, P; Durocher, F; Chenevix-Trench, G; Beesley, J; Chen, X; Rebbeck, T; Couch, F; Wang, X; Lindor, N; Fredericksen, Z; Pankratz, V S; Peterlongo, P; Bonanni, B; Fortuzzi, S; Peissel, B; Szabo, C; Mai, P L; Loud, J T; Lubinski, J

2012-01-01

121

Prevalence of methylene tetrahydrofolate reductase polymorphism in South Indian population  

Microsoft Academic Search

Prevalence of methylene tetrahydrofolate reductase (MTHFR) gene mutations in South Indian population was investigated from a total of 608 samples, 420 adults and 188 newborns. Detection of mutation was carried out focussing on the two most common mutations of the MTHFR gene (C677T and A1298C) using PCR- based RFLP method. T-allele frequency was almost simi- lar between the newborns and

A. Radha; Rama Devi; V. Govindaiah; G. Ramakrishna; S. M. Naushad

122

The 5, 10 methylenetetrahydrofolate reductase C677T mutation and risk of fetal loss: a case series and review of the literature  

PubMed Central

Background The true relationship between methylenetetrahydrofolate reductase C677T homozygosity and risk of recurrent spontaneous abortion is unknown, and it is unclear if women with these mutations should be anticoagulated during pregnancy. Objectives We report a series of 8 patients with this issue and review the current literature. Methods 8 patients (3 of whom were actively pregnant) were referred with histories of spontaneous fetal loss; hypercoaguability work-ups revealed each were homozygous for the MTHFR C677T mutation without other thrombophilias. Results In the 3 women who have conceived, treatment with LMW heparin during pregnancy led to two full-term births and one additional pregnancy without complication. For the 5 who have not, we recommended treatment with LMW heparin upon conception. Conclusion We provide evidence to support the relationship between MTHFR C677T mutations and recurrent fetal loss, and to suggest that anticoagulation of these patients during pregnancy can lead to a successful pregnancy outcome.

Altomare, Ivy; Adler, Alan; Aledort, Louis M

2007-01-01

123

Association of Corticosteroids and Factor V, Prothrombin, and MTHFR Gene Mutations With Avascular Osteonecrosis in Renal Allograft Recipients  

Microsoft Academic Search

The mechanism of posttransplantation avascular osteonecrosis (AVN) is controversial. Besides an increased bone marrow pressure due to reduced blood supply, enhanced coagulation has been considered. We investigated the associations of factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations as well as cumulative corticosteroid doses with AVN in renal allograft recipients. The records of 39 volunteer patients and 11 patients

A. Celik; D. Tekis; F. Saglam; S. Tunali; N. Kabakci; D. Ozaksoy; M. Manisali; M. A. Ozcan; M. Meral; H. Gülay; T. Camsari

2006-01-01

124

The methylenetetrahydrofolate reductase C677T mutation induces cell-specific changes in genomic DNA methylation and uracil misincorporation: A possible molecular basis for the site-specific cancer risk modification  

PubMed Central

The C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with a decreased risk of colon cancer while it may increase the risk of breast cancer. This polymorphism is associated with changes in intracellular folate cofactors, which may affect DNA methylation and synthesis via altered one-carbon transfer reactions. We investigated the effect of this mutation on DNA methylation and uracil misincorporation and its interaction with exogenous folate in further modulating these biomarkers of one-carbon transfer reactions in an in vitro model of the MTHFR 677T mutation in HCT116 colon and MDA-MB-435 breast adenocarcinoma cells. In HCT116 cells, the MTHFR 677T mutation was associated with significantly increased genomic DNA methylation when folate supply was adequate or high; however, in the setting of folate insufficiency, this mutation was associated with significantly decreased genomic DNA methylation. In contrast, in MDA-MB-435 cells, the MTHFR 677T mutation was associated with significantly decreased genomic DNA methylation when folate supply was adequate or high and with no effect when folate supply was low. The MTHFR 677T mutation was associated with a nonsignificant trend toward decreased and increased uracil misincorporation in HCT116 and MDA-MB-435 cells, respectively. Our data demonstrate for the first time a functional consequence of changes in intracellular folate cofactors resulting from the MTHFR 677T mutation in cells derived from the target organs of interest, thus providing a plausible cellular mechanism that may partly explain the site-specific modification of colon and breast cancer risks associated with the MTHFR C677T mutation.

Sohn, Kyoung-Jin; Jang, Hyeran; Campan, Mihaela; Weisenberger, Daniel J.; Dickhout, Jeffrey; Wang, Yi-Cheng; Cho, Robert C.; Yates, Zoe; Lucock, Mark; Chiang, En-Pei; Austin, Richard C.; Choi, Sang-Woon; Laird, Peter W.; Kim, Young-In

2009-01-01

125

Combined 677CC/1298AC genotypes of methylenetetrahydrofolate reductase (MTHFR ) reduce susceptibility to precursor B lymphoblastic leukemia in a Chinese population.  

PubMed

The methylenetetrahydrofolate reductase (MTHFR) encodes a major enzyme in folate metabolism. It has been suggested that two MTHFR polymorphisms, 677C>T and 1298A>C, influence risk of acute lymphoblastic leukemia (ALL). Most studies on relation of MTHFR polymorphisms to ALL susceptibility have been in pediatric populations because ALL is relatively rare in adults. Here, we report a case-control study of 127 Chinese patients with adult precursor B lymphoblastic leukemia (B-ALL) to examine correlation between the MTHFR polymorphisms and B-ALL susceptibility in adults. Our data show that although the prevalence of genotype 1298CC was significantly higher in the female patients than in the controls (P = 0.04), the differences in distributions of combined genotypes of 1298CC with either 677CC or 677CT between the cases and the controls were statistically insignificant. Haplotype analysis revealed no significant difference between the cases and the controls. The prevalence for joint MTHFR genotypes 677CC/1298AC was significantly lower in the female B-ALL cases than in the controls [odds ratio (OR) = 0.06, 95% CI = 0.00-0.53, P = 0.0033] and no differences among the men [OR = 0.71, 95% CI = 0.20-2.53, P = 0.55], suggesting that protective effects of combined MTHFR 677CC/1298AC genotypes on susceptibility of adult B-ALL are gender bias toward women with 677CC/1298AC women being at a 17-fold reduced odds to develop B-ALL. PMID:20374270

Lv, Ling; Wu, Cuie; Sun, Henjuan; Zhu, Saijuan; Yang, Yongchen; Chen, Xi; Fu, Hua; Bao, Liming

2010-03-30

126

Association of homocysteine and methylene tetrahydrofolate reductase (MTHFR C677T) gene polymorphism with coronary artery disease (CAD) in the population of North India  

PubMed Central

The implications of the methylene tetrahydrofolate reductase (MTHFR) gene and the level of homocysteine in the pathogenesis of coronary artery disease (CAD) have been extensively studied in various ethnic groups. Our aim was to discover the association of MTHFR (C677T) polymorphism and homocysteine level with CAD in north Indian subjects. The study group consisted of 329 angiographically proven CAD patients, and 331 age and sex matched healthy individuals as controls. MTHFR (C677T) gene polymorphism was detected based on the polymerase chain reaction and restriction digestion with HinfI. Total homocysteine plasma concentration was measured using immunoassay. T allele frequency was found to be significantly higher in patients than in the control group. We found significantly elevated levels of mean homocysteine in the patient group when compared to the control group (p = 0.00). Traditional risk factors such as diabetes, hypertension, smoking habits, a positive family history and lipid profiles (triglyceride, total cholesterol, HDL-cholesterol, LDL-cholesterol, VLDL-cholesterol), were found significantly associated through univariate analysis. Furthermore, multivariable logistics regression analysis revealed that CAD is significantly and variably associated with diabetes, hypertension, smoking, triglycerides and HDL-cholesterol. Our findings showed that MTHFR C677T polymorphism and homocysteine levels were associated with coronary artery disease in the selected population.

2010-01-01

127

Application of microarray-based method for methylenetetrahydrofolate reductase (MTHFR) polymorphisms in the risk of gastric carcinoma in east China population.  

PubMed

The microarrays were fabricated to explore the relationship between methylenetetrahydrofolate reductase (MTHFR) polymorphisms (C677T and A1298C) and risk of gastric carcinoma in Chinese population. The genomic DNA was isolated from 170 patients with gastric carcinoma and 140 age- and sex-matched control subjects. The frequencies of C677T genotype were: CC (47.9%), CT (40%), CT (12.1%) in control group and CC (35.9%), CT (45.9%), TT (18.2%) in gastric carcinoma group, respectively. The individuals with 677CT + TT or 677TT genotypes had a 1.67-fold (95% CI: 1.06-2.64) or 2.67-fold (95% CI: 1.382-5.341) increased risk of developing gastric carcinoma compared with those carrying 677CC genotype. The genotype of MTHFR gene A1298C allele was not significantly different between the two groups. We found that a joint effect exits between the MTHFR C677T and A1298C polymorphism on the risk of gastric carcinoma. Our results show that the single nucleotide polymorphisms in the MTHFR gene are associated with the risk of gastric carcinoma in the east China population. PMID:18019157

Li, Song; Ji, Meiju; He, Nongyue; Lu, Zuhong

2007-09-01

128

Improved Real-Time Multiplex Polymerase Chain Reaction Detection of Methylenetetrahydrofolate Reductase (MTHFR) 677C>T and 1298A>C Polymorphisms Using Nearest Neighbor Model-Based Probe Design  

PubMed Central

The disorders of folate metabolism caused by methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms may lead to several disease states including coronary heart disease, venous thrombosis, and several types of cancer. We have developed a real-time multiplex single-tube polymerase chain reaction procedure on the LightCycler for the detection of the two most commonly occurring variants, 677C>T and 1298A>C, in the MTHFR gene. An improved probe design, based on the nearest neighbor model for nucleic acid-probe duplex stability, resulted in a better separation (?Tm ? 10°C) of melting peaks of the wild-type and mutant alleles than that by the existing method (?Tm ? 3°C) for specimens heterozygous for the 1298A>C polymorphism. Of the 333 blood specimens analyzed by this procedure, we did not find any samples that gave ambiguous results. The specimens with homozygous mutation for one polymorphism were of the wild type for the other variant. The assay was validated by the comparison of the genotyping results of 50 blood specimens from the LightCycler polymerase chain reaction with the conventional restriction fragment length polymorphism procedures. There was 100% concordance of the test results obtained by the two techniques. This assay is reliable, economical, and can be performed by less trained technologists compared with the procedure performed by the conventional restriction fragment length polymorphism technique.

Agarwal, Raghunath P.; Peters, Stephen M.; Shemirani, Manijeh; von Ahsen, Nicolas

2007-01-01

129

Metabolic Syndrome and Insulin Resistance in Schizophrenia Patients Receiving Antipsychotics Genotyped for the Methylenetetrahydrofolate Reductase (MTHFR) 677C/T and 1298A/C Variants  

PubMed Central

Introduction The metabolic syndrome and insulin resistance represent growing concerns related to atypical antipsychotic (AAP) use as their incidence in the schizophrenia population is two to four fold higher than the general population. Reduced methylenetetrahydrofolate reductase (MTHFR) activity, resulting in aberrant folate metabolism and hyperhomocysteinemia, has been linked to cardiovascular disease and is unstudied in relation to AAP associated metabolic complications. Purpose To examine the relationship between MTHFR, metabolic syndrome, and insulin resistance in schizophrenia subjects receiving AAPs for ? 12 months. Methods Fifty-eight subjects were included in this cross-sectional analysis and screened for the metabolic syndrome, insulin resistance and MTHFR 677C/T and 1298 A/C genotype. Results Overall, 23 subjects (40%) met metabolic syndrome criteria. There were no differences in age, gender, race, or AAP exposure between genotype groups. For the 677 T allele carriers, 53% met metabolic syndrome criteria, compared to 23% in the CC genotype group, giving an OR = 3.7, (95% CI = 1.24 – 12.66, p = 0.02). Thus, for T allele subjects, the risk was almost four times greater, despite similar antipsychotic exposure. Both waist circumference and MTHFR genotype significantly predicted insulin resistance (F = 8.35, df = 5, 51, p < 0.0001), with these two terms interacting (F = 8.6, df = 2, p = 0.0006) suggesting TT subjects are at greater risk for insulin resistance with increasing central adiposity, which is independent of age, gender, BMI, or metabolic syndrome diagnosis. Conclusion Results should be taken cautiously due to the small sample size, but suggest the MTHFR 677C/T variant may predispose patients to AAP metabolic complications.

Ellingrod, Vicki L.; Miller, Del D.; Taylor, Stephan F.; Moline, Jessica; Holman, Timothy; Kerr, Jane

2008-01-01

130

Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease.  

PubMed Central

Mild hyperhomocysteinemia is an established risk factor for cardiovascular disease. Genetic aberrations in the cystathionine beta-synthase (CBS) and methylenetetrahydrofolate reductase (MTHFR) genes may account for reduced enzyme activities and elevated plasma homocysteine levels. In 15 unrelated Dutch patients with homozygous CBS deficiency, we observed the 833T-->C (I278T) mutation in 50% of the alleles. Very recently, we identified a common mutation (677C-->T; A-->V) in the MTHFR gene, which, in homozygous state, is responsible for the thermolabile phenotype and which is associated with decreased specific MTHRF activity and elevated homocysteine levels. We screened 60 cardiovascular patients and 111 controls for these two mutations, to determine whether these mutations are risk factors for premature cardiovascular disease. Heterozygosity for the 833T-->C mutation in the CBS gene was observed in one individual of the control group but was absent in patients with premature cardiovascular disease. Homozygosity for the 677C-->T mutation in the MTHFR gene was found in (15%) of 60 cardiovascular patients and in only 6 (approximately 5%) of 111 control individuals (odds ratio 3.1 [95% confidence interval 1.0-9.2]). Because of both the high prevalence of the 833T-->C mutation among homozygotes for CBS deficiency and its absence in 60 cardiovascular patients, we may conclude that heterozygosity for CBS deficiency does not appear to be involved in premature cardiovascular disease. However, a frequent homozygous mutation in the MTHFR gene is associated with a threefold increase in risk for premature cardiovascular disease.

Kluijtmans, L. A.; van den Heuvel, L. P.; Boers, G. H.; Frosst, P.; Stevens, E. M.; van Oost, B. A.; den Heijer, M.; Trijbels, F. J.; Rozen, R.; Blom, H. J.

1996-01-01

131

Identifying Mutations in Duplicated Functions in Saccharomyces cererrisiae: Recessive Mutations in HMGCoA Reductase Genes  

Microsoft Academic Search

The two yeast genes for 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, HMGl and HMG2, each encode a functional isozyme. Although cells bearing null mutations in both genes are inviable, cells bearing a null mutation in either gene are viable. This paper describes a method of screening for recessive mutations in the HMGl gene, the gene encoding the majority of HMG-CoA reductase activity

Michael E. Basson; Robert L. Moore; Jules O'Rear; Jasper Rine

132

A COMMON POLYMORPHISM IN THE METHYLENETETHYDROFOLATE REDUCTASE (MTHFR) GENE IS ASSOCIATED WITH QUANTITATIVE ULTRASOUND IN THOSE WITH LOW PLASMA FOLATE  

Technology Transfer Automated Retrieval System (TEKTRAN)

Our previously reported genome search in the Framingham Study using a quantitative ultrasound (QUS) phenotype found suggestive linkage on chromosome 1pter-1p36.3. This region contains several candidate genes for bone status, including the MTHFR gene. MTHFR catalyzes the conversion of 5,10-methylenet...

133

A COMMON POLYMORPHISM IN THE METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR) GENE IS ASSOCIATED WITH QUANTITATIVE ULTRASOUND IN THOSE WITH LOW PLASMA FOLATE  

Technology Transfer Automated Retrieval System (TEKTRAN)

A study of a polymorphism in the MTHFR gene, plasma folate, and bone phenotypes in 1632 individuals revealed that the genotype effect on BMD and quantitative ultrasound was dependent on the level of folate. Our findings support the hypothesis that the association between an MTHFR polymorphism and bo...

134

Methylenetetrahydrofolate reductase (MTHFR) gene 677C>T and 1298A>C polymorphisms are associated with differential apoptosis of leukemic B cells in vitro and disease progression in chronic lymphocytic leukemia.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) regulates the metabolism of folate and methionine, essential components of DNA synthesis and methylation. We investigated whether the two genetic MTHFR polymorphisms (677C>T and 1298A>C) are associated with an increased risk for chronic lymphocytic leukemia (CLL) or may predict disease progression. Moreover, we measured potential genotype effects on apoptosis of B-CLL cells.Allele frequencies and genotype distributions for both polymorphisms were not significantly different in 111 patients vs 92 healthy controls. While progression-free survival (PFS) was not significantly different in individuals with CLL including all stages, in patients with Binet stage A PFS was significantly longer in patients displaying the MTHFR 677CC (P=0.043) and the MTHFR 1298A/C or CC genotypes (P=0.019). In a multivariate analysis, MTHFR haplotype (677CC plus 1298CC or A/C) was the best independent prognostic factor for PFS compared with other known prognostic factors. Spontaneous apoptosis of B-CLL cells in vitro was significantly increased in the favorable risk group with MTHFR 677CC and MTHFR 1298AC, which may constitute the cellular basis of the observed associations. While MTHFR polymorphisms do not affect the risk for B-CLL, they may be independent prognostic markers that influence the PFS in patients with early-stage B-CLL. PMID:15385937

Nückel, H; Frey, U H; Dürig, J; Dührsen, U; Siffert, W

2004-11-01

135

Genetic susceptibility of methylenetetrahydrofolate reductase (MTHFR) gene C677T, A1298C, and G1793A polymorphisms with risk for bladder transitional cell carcinoma in men  

Microsoft Academic Search

We performed a case–control study of 158 bladder transitional cell carcinoma (TCC) cases and 316 controls to investigate the\\u000a association between methylenetetrahydrofolate reductase (MTHFR) C677T, A1298G, and G1793A polymorphisms and bladder cancer\\u000a susceptibility by polymerase chain reaction restriction fragment length polymorphism (PCR-RLFP) technique. The controls were\\u000a frequency-matched to the cases by age (±5 years), ethnicity, and smoking status. We also measured

Nayyer Shafiei; Shiva Safarinejad

136

Severe methylenetetrahydrofolate reductase (MTHFR) deficiency: a case report of nonclassical homocystinuria.  

PubMed

Severe methylenetetrahydrofolate reductase deficiency is an autosomal recessive metabolic disorder of folate metabolism causing elevated plasma homocysteine levels and homocystinuria (MIM 236250). A developmentally delayed 10-year-old girl presented with symptoms of progressive ataxia, dysarthria, tremor, mental status changes, and white-matter changes on magnetic resonance imaging. These changes occurred during a 3- to 4-month time period, with an acceleration of symptoms during 2 to 3 weeks. The patient was found to have extremely high serum homocysteine and low-normal serum methionine. She received treatment with vitamin B12, folate, betaine, multivitamins, and aspirin, with subsequent improvement of her symptoms and reduction in her serum homocysteine level. This case emphasizes the need to include homocystinuria in the differential diagnosis of children with acute/subacute neurological changes, particularly in the context of developmental delay. PMID:18658082

Bishop, Lisa; Kanoff, Richard; Charnas, Lawrence; Krenzel, Charles; Berry, Susan A; Schimmenti, Lisa A

2008-07-01

137

Cerebral Venous Thrombosis and Livedo Reticularis in a Case with MTHFR 677TT Homozygote  

PubMed Central

Hyperhomocysteinemia associated with methylene terahydrofolate reductase (MTHFR) mutation can be a risk factor for idiopathic cerebral venous thrombosis. We describe the first case of MTHFR 677TT homozygote with cerebral venous thrombosis and livedo reticularis. A 45-year-old man presented with seizures and mottled-like skin lesions, that were aggravated by cold temperature. Hemorrhagic infarct in the right frontoparietal area with superior sagittal sinus thrombosis was observed. He had hyperhomocysteinemia, low plasma folate level, and MTHFR 677TT homozygote genotype, which might be associated with livedo reticularis and increase the risk for cerebral venous thrombosis.

Lee, Jee-Young

2006-01-01

138

Elevated total plasma homocysteine and 667C{r_arrow}T mutation of the 5,10-methylenetetrahydrofolate reductase gene in thrombotic vascular disease  

SciTech Connect

Moderate elevation of total plasma homocysteine (tHcy) has been reported as an independent risk factor for thrombotic vascular disease, a well-known multifactorial disorder. Possible genetic causes of elevated tHcy include defects of the sulfur-containing amino acids metabolism due to deficiencies of cystathionine {Beta}-synthase, of 5,10-methylenetetrahydrofolate reductase (MTHFR), and of the enzymes of cobalamin metabolism. An impaired activity of MTHFR due to a thermolabile form of the enzyme has been observed in {le}28% of hyperhomocysteinemic patients with premature vascular disease. More recently, the molecular basis of such enzymatic thermolability has been related to a common mutation of the MTHFR gene, causing a C-to-T substitution at nt 677 (677C{r_arrow}T). This mutation was found in 38% of unselected chromosomes from 57 French Canadian individuals. The homozygous state for the mutation was present in 12% of these subjects and correlated with significantly elevated tHcy. Preliminary evidence indicates that the frequency of homozygotes for the 677C{r_arrow}T mutation may vary significantly in populations from different geographic areas. 5 refs., 2 tabs.

De Franchis, R.; Sebastio, G.; Andria, G. [Universita Federico II, Naples (Italy)] [and others

1996-07-01

139

Genetic susceptibility of methylenetetrahydrofolate reductase (MTHFR) gene C677T, A1298C, and G1793A polymorphisms with risk for bladder transitional cell carcinoma in men.  

PubMed

We performed a case-control study of 158 bladder transitional cell carcinoma (TCC) cases and 316 controls to investigate the association between methylenetetrahydrofolate reductase (MTHFR) C677T, A1298G, and G1793A polymorphisms and bladder cancer susceptibility by polymerase chain reaction restriction fragment length polymorphism (PCR-RLFP) technique. The controls were frequency-matched to the cases by age (± 5 years), ethnicity, and smoking status. We also measured serum levels of total homocysteine (tHcy), folate, and vitamin B12. It was found that the 1298AC (odds ratio, OR = 3.74; 95% confidence interval, CI = 2.34-5.47; P = 0.001) and 1298CC (OR = 3.46, 95% CI = 2.37-5.52; P = 0.001) genotypes of MTHFR A1298C were significantly associated with increased risk of bladder TCC. The MTHFR C677T and G1793A polymorphisms were not associated with bladder TCC. After stratification for grade and stage, we observed that the 677TT (OR = 4.47, 95% CI = 2.74-6.72; P = 0.001) and MTHFR 1298CC (OR = 4.78, 95% CI = 2.82-6.89; P = 0.001) genotypes of MTHFR were associated with increased risk of muscle-invasive bladder TCC. We also found that the MTHFR 677CT+1298AA genotypes were associated with an approximately 70% reduction in risk of bladder cancer (OR = 0.31; 95% CI = 0.15-0.68) compared to the combined referent genotype. There were 8 haplotypes and 16 haplotype genotypes based on these three variants. When we used the haplotypes and assumed that the 677T, 1298C, and 1793G alleles were risk alleles, the adjusted odds ratios increased as the number of risk alleles increased: 1.00 for 0-1 variant, 1.88 (1.4-2.7) for any two risk alleles and 2.07 (1.6-2.8) for any three risk alleles. Serum tHcy levels were significantly higher in carriers of the 677T, 1298C, and 1793G alleles compared to noncarriers (all P < 0.01). There was no significant correlation between serum levels of tHcy and folate and bladder cancer risk. Further studies in larger samples size and different ethnicity are required to confirm our findings. PMID:21046286

Safarinejad, Mohammad Reza; Shafiei, Nayyer; Safarinejad, Shiva

2010-10-29

140

Meta- and Pooled Analyses of the Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism and Colorectal Cancer: A HuGE-GSEC Review  

PubMed Central

Worldwide, over 1 million cases of colorectal cancer (CRC) were reported in 2002, with a 50% mortality rate, making CRC the second most common cancer in adults. Certain racial/ethnic populations continue to experience a disproportionate burden of CRC. A common polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene has been associated with a lower risk of CRC. The authors performed both a meta-analysis (29 studies; 11,936 cases, 18,714 controls) and a pooled analysis (14 studies; 5,068 cases, 7,876 controls) of the C677T MTHFR polymorphism and CRC, with stratification by racial/ethnic population and behavioral risk factors. There were few studies on different racial/ethnic populations. The overall meta-analysis odds ratio for CRC for persons with the TT genotype was 0.83 (95% confidence interval (CI): 0.77, 0.90). An inverse association was observed in whites (odds ratio = 0.83, 95% CI: 0.74, 0.94) and Asians (odds ratio = 0.80, 95% CI: 0.67, 0.96) but not in Latinos or blacks. Similar results were observed for Asians, Latinos, and blacks in the pooled analysis. The inverse association between the MTHFR 677TT polymorphism and CRC was not significantly modified by smoking status or body mass index; however, it was present in regular alcohol users only. The MTHFR 677TT polymorphism seems to be associated with a reduced risk of CRC, but this may not hold true for all populations.

Taioli, E.; Garza, M. A.; Ahn, Y. O.; Bishop, D. T.; Bost, J.; Budai, B.; Chen, K.; Gemignani, F.; Keku, T.; Lima, C. S. P.; Le Marchand, L.; Matsuo, K.; Moreno, V.; Plaschke, J.; Pufulete, M.; Thomas, S. B.; Toffoli, G.; Wolf, C. R.; Moore, C. G.; Little, J.

2009-01-01

141

Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with osteoporotic vertebral fractures, but is a weak predictor of BMD  

Microsoft Academic Search

Osteoporosis is a common disease with a strong genetic component. Linkage studies have suggested linkage between BMD and loci on chromosome 1. The MTHFR gene is located on chromosome 1. MTHFR catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methylenetetrahydrofolate, which is used for homocysteine methylation to methionine. The rare genotype (TT) of the C677T polymorphism has previously been demonstrated to be

Morten M. Villadsen; Mathias H. Bünger; Mette Carstens; Liselotte Stenkjćr; Bente L. Langdahl

2005-01-01

142

Plasma Homocyst(e)ine Concentration, But Not MTHFR Genotype, Is Associated With Variation in Carotid Plaque Area  

Microsoft Academic Search

Background and Purpose—Elevated plasma homocyst(e)ine (H(e)) concentration is associated with premature athero- sclerosis. A common cause of elevated plasma H(e) concentration is a thermolabile mutation (677T) in the gene encoding methylenetetrahydrofolate reductase (MTHFR). We sought to determine whether plasma H(e) concentration or MTHFR genotype would be more strongly associated with carotid plaque area (CPA), a potential intermediate phenotype of atherosclerosis.

J. David Spence; M. Rene Malinow; Peter A. Barnett; Ali J. Marian; David Freeman; Robert A. Hegele

143

Role of polymorphisms in factor V (FV Leiden), prothrombin, plasminogen activator inhibitor type-1 (PAI-1), methylenetetrahydrofolate reductase (MTHFR) and cystathionine ?-synthase (CBS) genes as risk factors for thrombophilias.  

PubMed

Thrombophilias are defined as a predisposition to thrombosis due to hematological changes which induce blood hypercoagulability; they can be inherited or acquired. They are individually characterized by a large phenotypic variability, even when they occur within the same family. Hereditary thrombophilias are, in most cases, due to changes related to physiological coagulation inhibitors or mutations in the genes of coagulation factors. High levels of plasma homocysteine may also be responsible for vaso-occlusive episodes and may have acquired (nutritional deficiencies of folate and vitamins B6 and B12) and/or genetic causes (mutations in the genes responsible for expression of enzymes involved in the intracellular metabolism of homocysteine). Considering that: (1) thromboses are events of multigenic and multifactorial etiopathology; (2) the presence of mutations in several genes significantly increases the risk of their occurrence; (3) the vascular territory (venous and/or arterial) affected involves different pathophysiological mechanisms and treatments, knowledge of genetic variants that may contribute to the risk and variability of the phenotypic manifestations of these diseases is extremely important. This understanding may provide support for a more individualized and therefore more effective treatment for thrombophilia carriers. Thus, this mini-review aims to address a comprehensive summary of thrombophilias and thrombosis, and discuss the role of polymorphisms in Factor V (FV Leiden), Prothrombin, Plasminogen activator inhibitor type-1 (PAI-1), Methylenetetrahydrofolate reductase (MTHFR) and Cystathionine ?-synthase (CBS) genes as risk factors for thrombophilias. PMID:22512572

Miranda-Vilela, A L

2012-09-01

144

I polimorfismi della metilentetraidrofolatoreduttasi (MTHFR) nel trattamento con methotrexate di pazienti con artrite reumatoide. Revisione della letteratura ed esperienza personale* Methylenetetrahydrofolate reductase polymorphisms in methotrexate treatment of rheumatoid arthritis patients. Review of the literature and personal experience  

Microsoft Academic Search

SUMMARY Methotrexate is still a mainstay of rheumatoid arthritis treatment, but a significant variability in drug response is ob- served among patients. It has been proposed that C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase (MTHFR), an enzyme involved in the folate pathway, could be related to its efficacy and toxicity. Many stud- ies have investigated the predictive value of such

M. Taraborelli; L. Andreoli; S. Archetti; M. Ferrari; R. Cattaneo; A. Tincani

145

Drosophila dihydrofolate reductase mutations confer antifolate resistance to mammalian cells  

Microsoft Academic Search

Antifolates, such as methotrexate, are used to inhibit dihydrofolate reductase (DHFR), an enzyme essential for the biosynthesis of thymidylate, purines, and several amino acids. DHFR sequences corresponding to mutations found in a methotrexate resistant Drosophila S3 cell line (L30Q), a methotrexate resistant fly population (K31P, Q134K), as well as predicted in silico (L22R) were expressed in Chinese Hamster Ovary (CHO)

Joslynn G. Affleck; Khalid M. Al-Batayneh; Katerina Neumann; Susan P. C. Cole; Virginia K. Walker

2006-01-01

146

Severe methylenetetrahydrofolate reductase deficiency revealed by a pulmonary embolism in a young adult.  

PubMed

Deficiency in methylenetetrahydrofolate reductase (MTHFR), the enzyme involved in the remethylation of homocysteine to methionine using methyltetrahydrofolate as cofactor, induces hyperhomocysteinaemia, homocysteinuria, hypomethioninaemia and low methylfolate levels. Diagnosis usually occurs during infancy because of various neurological abnormalities. We report MTHFR deficiency diagnosed in an adult woman after a pulmonary embolism. Her adult sister, intellectually retarded, suffered from the same disease. Molecular analysis of the MTHFR gene exhibited four different mutations (two missense mutations, one exon skipping and C677T). The impact of these mutations was analysed through the biological abnormalities in the parents and children. PMID:12406076

Tonetti, Carole; Ruivard, Marc; Rieu, Virginie; Zittoun, Jacqueline; Giraudier, Stephane

2002-11-01

147

Prevalence of MTHFR gene polymorphisms (C677T and A1298C) among Tamilians.  

PubMed

We have investigated the incidence of the C677T and A1298C methylene tetrahydrofolate reductase (MTHFR) gene single nucleotide polymorphisms (SNPs) in the South Indian Tamil Nadu population with a total number of 72 individuals. The MTHFR genotyping was performed using the polymerase chain reaction followed by restriction enzyme analysis. Homozygosity for the MTHFR A1298C SNP was detected in 15.3% (11/72) of the individuals tested, and 47.2% (34/72) were heterozygous for this SNP. Homozygosity for the C677T MTHFR SNP was detected in 1.38%(1/72), and the frequency of the C677T heterozygotes was 18.1%(13/72). When we analyzed the combined frequency of the two SNPs, the frequency of double heterozygosity was19.6%, and the frequency of double homozygosity was completely absent among the study group. The 'C' allele frequency for MTHFR A1298C was 0.389, and the 'T' allele frequency for C677T mutation was 0.104. Out of the 72 individuals included in the study, 52 were acute myocardial infarction (AMI) patients and 20 were healthy individuals with no documented history of heart disease. The results of this study indicate that the MTHFR A1298C SNP is more prevalent among the Tamilians when compared to the MTHFR C677T SNP, suggesting a possible role of MTHFR A1298C in the pathogenesis of heart diseases. PMID:15351230

Angeline, T; Jeyaraj, Nirmala; Granito, Selena; Tsongalis, Gregory J

2004-10-01

148

Prevalence of Methylenetetrahydrofolate Reductase Polymorphisms in Young Patients with Inflammatory Bowel Disease  

Microsoft Academic Search

Inflammatory bowel disease (IBD) has been related to mutations of methylenetetrahydrofolate reductase (MTHFR), a critical\\u000a enzyme in the metabolism of folate and methionine, both of which are important factors in DNA methylation and synthesis. A\\u000a mutated MTHFR genotype was associated with increased toxicity of methotrexate treatment. The objective of this study was to\\u000a verify, in a population of young patients

Gabriele Stocco; Stefano Martelossi; Franca Sartor; Giuseppe Toffoli; Paolo Lionetti; Arrigo Barabino; Massimo Fontana; Giuliana Decorti; Fiora Bartoli; Tullio Giraldi; Alessandro Ventura

2006-01-01

149

MTHFR C677T and A1298C gene polymorphisms and hyperhomocysteinemia as risk factors of diabetic nephropathy in type 2 diabetes patients  

Microsoft Academic Search

Point mutations in methylenetetrahydrofolate reductase (MTHFR) and hyperhomocysteinemia were implicated in the pathogenesis of diabetic nephropathy (DN) in many ethnic groups. This study addressed the association of C677T and A1298C single nucleotide polymorphisms (SNPs) of MTHFR gene with DN in Tunisian type 2 diabetes (T2DM) patients. Study subjects comprised 93 DN patients, 267 patients with normoalbuminuria, and 400 control subjects.

Nabil Mtiraoui; Intissar Ezzidi; Molka Chaieb; Hela Marmouche; Zied Aouni; Arbi Chaieb; Touhami Mahjoub; Martine Vaxillaire; Wassim Y. Almawi

2007-01-01

150

Impact of methylenetetrahydrofolate reductase (MTHFR) codon (677) and methionine synthase (MS) codon (2756) on risk of cervical carcinogenesis in North Indian population.  

PubMed

Cervical cancer continues to be the most common cause of death among women in developing countries. Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS) are critical enzymes of folate metabolic pathways. In this work, we have conducted a case-control study to assess the role of these two polymorphisms in cervical cancer development. We obtained blood samples from 200 women with cervical cancer and from equal matched controls and analysed using PCR-RFLP method. We found that the methylenetetrahydrofolate reductase variant CT and CT+TT genotypes decreased cervix cancer risk, statistically significant (OR:0.30, 95% CI: 0.18-0.51, P<0.001 for CT and OR:0.29, 95% CI: 0.18-0.49, P=0.0000006 for CT+TT). Similarly in those patients who used oral contraceptive with variant CT genotype, there was statistically highly significant reduced risk of cervix cancer (OR:0.25, 95% CI: -0.12-0.49, P<0.001) of methylenetetrahydrofolate reductase gene. For the methionine synthase, 2756 variant AG and AG+GG genotypes were similarly associated with highly significant reduced risk of cervix cancer (OR: 0.13, 95% CI: 0.07-0.26, P<0.001 for AG, and OR: 0.15, 95% CI: 0.08-0.27, P<0.001 for AG+GG) genotypes. In conclusion, our study suggested that methylenetetrahydrofolate reductase and methionine synthase polymorphisms might have protective effect on the risk of cervical cancer in the North Indian women. PMID:18351371

Shekari, Mohammad; Sobti, Ranbir Chander; Kordi Tamandani, Dor Mohammad; Suri, Vanita

2008-03-20

151

Homocysteine and methylenetetrahydrofolate reductase genotype: association with risk of coronary heart disease and relation to inflammatory, hemostatic, and lipid parameters  

Microsoft Academic Search

Aim: It has been suggested that homocysteine (tHcy) levels and methylenetetrahydrofolate reductase (MTHFR) genotype are primary risk factors for coronary heart disease (CHD). We performed a case-control study to investigate whether tHcy levels and MTHFR genotype (677 C?T mutation and 1298 A?C mutation) are associated with CHD under special consideration of the possibility for confounding. Methods: German speaking patients aged

D. Rothenbacher; H. G. Fischer; A. Hoffmeister; M. M. Hoffmann; W. März; G. Bode; J. Rosenthal; W. Koenig; H. Brenner

2002-01-01

152

No association between MTHFR gene polymorphism and diabetic nephropathy in Japanese type II diabetic patients with proliferative diabetic retinopathy.  

PubMed

The development of diabetic nephropathy shows marked variation among individuals. Not only hyperglycemia, but also genetic factors may contribute to the development of diabetic nephropathy. Methylenetetrahydrofolate reductase (MTHFR) is involved in remethylation of homocysteine to methionine. Decreased activity of MTHFR which can result in hyperhomocysteinemia may lead to cerebrovascular disease and coronary artery disease. Recently, a common C to T mutation at nucleotide position 677 of the MTHFR gene (MTHFR677CT) has been reported to be correlated with hyperhomocysteinemia and the severity of coronary artery disease as macroangiopathy. In the present study, we recruited 173 of Japanese type II diabetic patients with proliferative diabetic retinopathy who would be exposed to long-term hyperglycemia, and examined the contribution of the MTHFR gene polymorphism to the development of diabetic nephropathy as microangiopathy. The frequency of the mutated allele was 43.3% in patients with nephropathy (n = 105) versus 41.9% in those without nephropathy (n = 68). The genotype frequencies were +/+, 16.2%; +/-, 54.3%; -/-, 29.5% in patients with nephropathy versus +/+, 13.2%; +/-, 57.4%; -/-, 29.4% in those without nephropathy (+ indicates the presence of the mutation). The MTHFR genotype and allele frequencies were not significantly different between patients with and without nephropathy. Therefore, we conclude that the MTHFR gene polymorphism is not associated with the development of diabetic nephropathy in Japanese type II diabetic patients. PMID:10765003

Fujita, H; Narita, T; Meguro, H; Ishii, T; Hanyu, O; Suzuki, K; Kamoi, K; Ito, S

153

Molecular analysis of factor V Leiden, factor V Hong Kong, factor II G20210A, methylenetetrahydrofolate reductase C677T, and A1298C mutations related to Turkish thrombosis patients.  

PubMed

Inherited gene disorders related to the hemostatic system have been documented as risk factors for thrombosis. The roles of factor V Hong Kong (FV Hong Kong), factor V Leiden (FV Leiden), factor II G20210A (FII G20210A), methylenetetrahydrofolate reductase (MTHFR) C677T, and MTHFR A1298C mutations in Turkish patients with thrombosis (270 patients) compared with healthy controls (114 subjects) were evaluated. Polymerase chain reaction-based restriction enzyme analysis was carried out to screen these mutations, and single-strand conformation analysis was established to identify variations using the primers selected for restriction enzyme analysis studies. As a result, a significant relationship was determined among FV Leiden, FII G20210A, and thrombosis. The FV Hong Kong mutation was observed in only 2 patients with pulmonary vein thrombosis who are FV Leiden/FV Hong Kong compound heterozygous for FV gene. MTHFR C677T and A1298C were equally distributed in the patient group compared with the control group. All named mutations were also identified with single-strand conformation analysis, but a new variant/polymorphism during studies was not found. Because some inherited abnormalities are associated with thromboembolic disorders, determining the mutations and gene-to-gene interactions in patients with thrombosis history has a great impact on diagnosis and treatment of these diseases. PMID:17911197

Dölek, Bilgen; Eraslan, Serpil; Ero?lu, Sevim; Kesim, Belgin Eroglu; Ulutin, Turgut; Yalçiner, Altan; Laleli, Yahya R; Gözükirmizi, Nermin

2007-10-01

154

Nonsense mutations in the dihydrofolate reductase gene affect RNA processing  

SciTech Connect

Steady-state dihydrofolate reductase (dhfr) mRNA levels were decreased as a result of nonsense mutations in the dhfr gene. Thirteen DHFR-deficient mutants were isolated after treatment of Chinese hamster ovary cells with UV irradiation. The positions of most point mutations were localized by RNA heteroduplex mapping, the mutated regions were isolated by cloning or by enzymatic amplification, and base changes were determined by DNA sequencing. Two of the mutants suffered large deletions that spanned the entire dhfr gene. The remaining 11 mutations consisted of nine single-base substitutions, one double-base substitution, and one single-base insertion. All of the single-base substitutions took place at the 3' position of a pyrimidine dinucleotide, supporting the idea that UV mutagenesis proceeds through the formation of pyrimidine dimers in mammalian cells. Of the 11 point mutations, 10 resulted in nonsense codons, either directly or by a frameshift, suggesting that the selection method favored a null phenotype. An examination of steady-state RNA levels in cells carrying these mutations and a comparison with similar data from other dhfr mutants showed that translation termination mutations in any of the internal exons of the gene gave rise to a low-RNA phenotype, whereas missense mutations in these exons or terminations in exon 6 (the final exon) did not affect dhfr mRNA levels. Nuclear run-on experiments showed that transcription of the mutant genes was normal. The stability of mature dhfr mRNA also was not affected, since (i) decay rates were the same in wild-type and mutant cells after inhibition of RNA synthesis with actinomycin D and (ii) intronless minigene versions of cloned wild-type and nonsense mutant genes were expressed equally after stable transfection.

Urlaub, G.; Mitchell, P.J.; Ciudad, C.J.; Chasin, L.A. (Columbia Univ., New York, NY (USA))

1989-07-01

155

Stromelysin-1 5A\\/6A and eNOS T-786C Polymorphisms, MTHFR C677T and A1298C Mutations, and Cigarette-Cannabis Smoking: A Pilot, Hypothesis-Generating Study of Gene-Environment Pathophysiological Associations With Buerger’s Disease  

Microsoft Academic Search

Buerger’s disease (BD) etiologies are poorly understood. Beyond smoking cessation, medical-surgical treatments have limited success. We hypothesized that mutations associated with arterial vasospasm (stromelysin-1 5A\\/6A, eNOS T-786C) and C677T-A1298C methylene tetrahydrofolate reductase (MTHFR) interacted with cigarette-cannabis smoking, reducing vasodilatory nitric oxide (NO), promoting arterial spasm-thrombosis. Of 21 smoking BD patients (14 men [2 siblings], 7 women; 20 white, 1 African-American),

Charles J. Glueck; Mofiz Haque; Magdalena Winarska; Swapna Dharashivkar; Robert N. Fontaine; Binghua Zhu; Ping Wang

2006-01-01

156

Molecular beacons: a new approach for semiautomated mutation analysis  

Microsoft Academic Search

Molecular beacons are oligonucleotide probes that be- come fluorescent upon hybridization. We designed molecular beacons to detect a point mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, a mutation that has been related to an increased risk for cardiovascular disease and neural tube defects. The application of molecular beacons enables fast, semi- automated, accurate mutation detection. Moreover, the procedure is performed

Belinda A. J. Giesendorf; Jacqueline A. M. Vet; Sanjay Tyagi; Ewald J. M. G. Mensink; Frans J. M. Trijbels; Henk J. Blom

157

Recurrent ischemic strokes in a young celiac woman with MTHFR gene mutation  

PubMed Central

Celiac disease (CD) is frequently associated with neurological disorders, but very few reports concern the association with ischemic stroke. A 26-year-old woman affected by CD with secondary amenorrhea, carrier of a homozygous 5,10-methylenetetrahydrofolate reductase mutation with hyperhomocysteinemia, was affected by two occipital ischemic strokes within a period of 5 mo. At the time of the second stroke, while she was being treated with folic acid, acetylsalicylic acid and a gluten-free diet, she had left hemianopsia, left hemiparesthesias, and gait imbalance. Brain magnetic resonance imaging showed a subacute right occipital ischemic lesion, which was extended to the dorsal region of the right thalamus and the ipsilateral thalamo-capsular junction. Antitransglutaminase and deamidated gliadin peptide antibodies were no longer present, while antinuclear antibodies, antineuronal antibodies and immune circulating complexes were only slightly elevated. Since the patient was taking folic acid, her homocysteine ??levels were almost normal and apparently not sufficient alone to explain the clinical event. A conventional cerebral angiography showed no signs of vasculitis. Finally, rare causes of occipital stroke in young patients, such as Fabry’s disease and mitochondrial myopathy, encephalomyopathy, lactic acidosis and stroke-like symptoms, were also excluded by appropriate tests. Thus, the most probable cause for the recurrent strokes in this young woman remained CD, although the mechanisms involved are still unknown. The two main hypotheses concern malabsorption (with consequent deficiency of vitamins known to exert neurotrophic and neuroprotective effects) and immune-mediated mechanisms. CD should be kept in mind in the differential diagnosis of ischemic stroke in young patients.

Fabbri, Elisa; Rustignoli, Lisa; Muscari, Antonio; Puddu, Giovanni M; Guarino, Maria; Rinaldi, Rita; Minguzzi, Elena; Caio, Giacomo; Zoli, Marco; Volta, Umberto

2012-01-01

158

Recurrent ischemic strokes in a young celiac woman with MTHFR gene mutation.  

PubMed

Celiac disease (CD) is frequently associated with neurological disorders, but very few reports concern the association with ischemic stroke. A 26-year-old woman affected by CD with secondary amenorrhea, carrier of a homozygous 5,10-methylenetetrahydrofolate reductase mutation with hyperhomocysteinemia, was affected by two occipital ischemic strokes within a period of 5 mo. At the time of the second stroke, while she was being treated with folic acid, acetylsalicylic acid and a gluten-free diet, she had left hemianopsia, left hemiparesthesias, and gait imbalance. Brain magnetic resonance imaging showed a subacute right occipital ischemic lesion, which was extended to the dorsal region of the right thalamus and the ipsilateral thalamo-capsular junction. Antitransglutaminase and deamidated gliadin peptide antibodies were no longer present, while antinuclear antibodies, antineuronal antibodies and immune circulating complexes were only slightly elevated. Since the patient was taking folic acid, her homocysteine ??levels were almost normal and apparently not sufficient alone to explain the clinical event. A conventional cerebral angiography showed no signs of vasculitis. Finally, rare causes of occipital stroke in young patients, such as Fabry's disease and mitochondrial myopathy, encephalomyopathy, lactic acidosis and stroke-like symptoms, were also excluded by appropriate tests. Thus, the most probable cause for the recurrent strokes in this young woman remained CD, although the mechanisms involved are still unknown. The two main hypotheses concern malabsorption (with consequent deficiency of vitamins known to exert neurotrophic and neuroprotective effects) and immune-mediated mechanisms. CD should be kept in mind in the differential diagnosis of ischemic stroke in young patients. PMID:22807619

Fabbri, Elisa; Rustignoli, Lisa; Muscari, Antonio; Puddu, Giovanni M; Guarino, Maria; Rinaldi, Rita; Minguzzi, Elena; Caio, Giacomo; Zoli, Marco; Volta, Umberto

2012-07-14

159

The association between methylene-tetrahydrofolate reductase gene polymorphism and lung cancer risk  

Microsoft Academic Search

This study aimed to determine the relation between methylene-tetrahydrofolate reductase (MTHFR) gene polymorphism and lung\\u000a cancer risk and the frequency of this polymorphism. The study involved 64 lung cancer patients (the study group) with definitive\\u000a diagnosis and 61 noncancerous subjects (the control group). MTHFR C677T and A1298C mutation analysis was made using DNA isolated\\u000a from peripheric blood and multiplex PCR

Sulhattin Arslan; Sule Karadayi; Malik Ejder Yildirim; Ozturk Ozdemir; Ibrahim Akkurt

2011-01-01

160

Heterogeneity in the prevalence of methylenetetrahydrofolate reductase gene polymorphisms in women of different ethnic groups  

Microsoft Academic Search

Objective To determine the prevalence of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms in women of different ethnic groups and to relate these common mutations to plasma homocysteine, red cell folate, and serum folate. Design A one-time fasting blood sample was obtained for MTHFR genotype (C677T and A1298C) determinations (n=433). Serum folate, red cell folate, and homocysteine analyses were performed in nonfolic

Setareh Torabian Esfahani; Edward A Cogger; Marie A Caudill

2003-01-01

161

Functional characterization of human methylenetetrahydrofolate reductase in Saccharomyces cerevisiae.  

PubMed

Human methylenetetrahydrofolate reductase (MTHFR, EC 1.5.1.20) catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. 5-Methyltetrahydrofolate is a major methyl donor in the remethylation of homocysteine to methionine. Impaired MTHFR can cause high levels of homocysteine in plasma, which is an independent risk factor for vascular disease and neural tube defects. We have functionally characterized wild-type and several mutant alleles of human MTHFR in yeast, Saccharomyces cerevisiae. We have shown that yeast MET11 is a functional homologue of human MTHFR. Expression of the human MTHFR cDNA in a yeast strain deleted for MET11 can restore the strain's MTHFR activity in vitro and complement its methionine auxotrophic phenotype in vivo. To understand the domain structure of human MTHFR, we have truncated the C terminus (50%) of the protein and demonstrated that expressing an N-terminal human MTHFR in met11(-) yeast cells rescues the growth phenotype, indicating that this region contains the catalytic domain of the enzyme. However, the truncation leads to the reduced protein levels, suggesting that the C terminus may be important for protein stabilization. We have also functionally characterized four missense mutations identified from patients with severe MTHFR deficiency and two common missense polymorphisms found at high frequency in the general population. Three of the four missense mutations are unable to complement the auxotrophic phenotype of met11(-) yeast cells and show less than 7% enzyme activity of the wild type in vitro. Both of the two common polymorphisms are able to complement the growth phenotype, although one exhibited thermolabile enzyme activity in vitro. These results shall be useful for the functional characterization of MTHFR mutations and analysis structure/function relationship of the enzyme. PMID:10551815

Shan, X; Wang, L; Hoffmaster, R; Kruger, W D

1999-11-12

162

Children With Stroke: Polymorphism of the MTHFR Gene, Mild Hyperhomocysteinemia, and Vitamin Status  

Microsoft Academic Search

The aim of this study was to investigate a possible association among the thermolabile polymorphism, nucleotide 677 cytosine to thymidine point mutation (677 C?T) of the methylenetetrahydrofolate reductase (MTHFR) gene, hyperhomocysteinemia, serum folate, vitamins B12 and B6, and stroke in children. Allele and genotype frequencies for the 677 C?T polymorphism in 21 children with stroke and 28 healthy children of

Esther Cardo; Eugčnia Monrós; Catrina Colomé; Rafael Artuch; Jaume Campistol; Mercč Pineda; M. Antňnia Vilaseca

2000-01-01

163

Serum Homocysteine, MTHFR Gene Polymorphism, and Carotid Intimal-Medial Thickness in NIDDM Subjects  

Microsoft Academic Search

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

Alfredo Mazza; Corradino Motti; Angela Nulli; Anna Pastore; Felicita Andreotti; Vincenzo Ammaturo; Pasquale Bianco; Elena Santoro; Giorgio Federici; Claudio Cortese

1999-01-01

164

Methylenetetrahydrofolate Reductase 677C.T and Methionine Synthase 2756A.G Mutations: No Impact on Survival, Cognitive Functioning, or Cognitive Decline in Nonagenarians  

Microsoft Academic Search

Background. Several reports have shown an association between homocysteine, cognitive functioning, and survival among the oldest-old. Two common polymorphisms in the genes coding for methylenetetrahydrofolate reductase (MTHFR 677C.T) and methionine synthase (MTR 2756A.G) have an impact on plasma homocysteine level. Methods. We examined the effect of the MTHFR 677C.T and MTR 2756A.G genotypes on baseline cognitive functioning, cognitive decline over

Lise Bathum; Jacob von Bornemann Hjelmborg; Lene Christiansen; Matt McGue; Bernard Jeune; Kaare Christensen

165

Lack of association of methylenetetrahydrofolate reductase 677C>T mutation with coronary artery disease in a Pakistani population  

PubMed Central

Pakistanis belong to the South Asian population which has the highest known rate of coronary artery disease. Folic acid deficiency also appears to be highly prevalent in this population. Methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism decreases the activity of this enzyme and can be associated with mild to moderate hyperhomocysteinemia in homozygotes, particularly when there is folic acid deficiency, as well as with coronary artery disease. To assess the value of genotyping the MTHFR 677C>T dimorphism, we carried out a case-control study of dimorphism 677C>T for putative association with myocardial infarction (MI) among Pakistani nationals. We investigated a sample population of 622 Pakistanis consisting of 225 controls and 397 patients with clinical diagnosis of acute MI (AMI). MTHFR C677T alleles were determined by assays based on polymerase chain reaction and restriction endonuclease analysis. Frequencies of C alleles were 0.87 among controls and 0.86 among AMI patients. The MTHFR 677C>T dimorphism showed no association with MI (?2 = 0.25, 1df, P=0.62), serum levels of folate and vitamin B12 and plasma level of vitamin B6. A significant association, however, was found between homozygous 677T genotype and plasma levels of homocysteine. Multivariate analysis of the data showed that in case of log homocysteine, age and MTHFR genotypes were significantly different (P<0.001). In case of B12, smoking and age were found to be statistically significant (P<0.001), while in case of serum folate only smoking was found to be significant (P<0.001). The results indicate that MTHFR 677C>T polymorphism, though associated with homocysteine levels, confers no significant risk of coronary artery disease in the Pakistani population investigated here. We suggest that the higher incidence of AMI in South Asia occurs through mechanisms other than the MTHFR related pathways.

Iqbal, M Perwaiz; Fatima, Tasneem; Parveen, Siddiqa; Yousuf, Farzana A; Shafiq, Majid; Mehboobali, Naseema; Khan, Abrar H; Azam, Iqbal; Frossard, Philippe M

2005-01-01

166

Frequency of the Methylenetetrahydrofolate REDUCTASE 677CT and 1298AC mutations in an Iranian Turkish female population  

PubMed Central

ABSTRACT Introduction: Gene-environmental interactions in the pathway of folate metabolism influence greatly the embryonic development. Individual specific MTHFR 677C/T and 1298A/C mutations are known as risk factors for predisposition to human disorders. Therefore, we studied the frequencies of the MTHFR 677CT and 1298AC mutations in a female general population from Iranian Azeri Turkish. Material and methods: We studied 108 unrelated women from Iranian Azeri Turkish general population. Genomic DNA was extracted using standard procedure. The MTHFR 677CT and 1298AC mutations determined by PCR-RFLP method. Outcomes: The frequencies (percent) at position 677 for C and T alleles were 159(74%), 57(26%), and for CC, CT, and TT genotypes were 59(54.6%), 41(38%), and 8(7.41%) respectively. The frequencies (percent) at position 1298 for A and C alleles were 136(63%), 80(37%), and for AA, AC, and CC genotypes were 43(39.8%), 50(46.3%), and 15(13.9%) respectively. Conclusions: The frequency of MTHFR 677 C and T alleles were 0.74 and 0.26 while that of MTHFR 1298 A and C alleles were 0.63 and 0.37 in present study, respectively. This is the first report in its own kind in Iranian Azeri Turkish women.

BAGHERI, Morteza; ABDI RAD, Isa

2010-01-01

167

Frequency of the Methylenetetrahydrofolate REDUCTASE 677CT and 1298AC mutations in an Iranian Turkish female population.  

PubMed

Introduction: Gene-environmental interactions in the pathway of folate metabolism influence greatly the embryonic development. Individual specific MTHFR 677C/T and 1298A/C mutations are known as risk factors for predisposition to human disorders. Therefore, we studied the frequencies of the MTHFR 677CT and 1298AC mutations in a female general population from Iranian Azeri Turkish.Material and methods: We studied 108 unrelated women from Iranian Azeri Turkish general population. Genomic DNA was extracted using standard procedure. The MTHFR 677CT and 1298AC mutations determined by PCR-RFLP method.Outcomes: The frequencies (percent) at position 677 for C and T alleles were 159(74%), 57(26%), and for CC, CT, and TT genotypes were 59(54.6%), 41(38%), and 8(7.41%) respectively. The frequencies (percent) at position 1298 for A and C alleles were 136(63%), 80(37%), and for AA, AC, and CC genotypes were 43(39.8%), 50(46.3%), and 15(13.9%) respectively.Conclusions: The frequency of MTHFR 677 C and T alleles were 0.74 and 0.26 while that of MTHFR 1298 A and C alleles were 0.63 and 0.37 in present study, respectively. This is the first report in its own kind in Iranian Azeri Turkish women. PMID:21977149

Bagheri, Morteza; Abdi Rad, Isa

2010-07-01

168

Head and Neck Cancer Susceptibility: A Genetic Marker in the Methylenetetrahydrofolate Reductase Gene  

Microsoft Academic Search

Progress in the elucidation of molecular genetic changes that lead to the development of tumors should soon bring novel diagnostic and therapeutic procedures into clinical practice. In this respect, methylenetetrahydrofolate reductase (MTHFR) plays a central role in folate metabolism that affects DNA methylation and synthesis. DNA methylation is an epigenetic feature that influences cellular development and function. Germ line mutation

Nelofar Kureshi; Shehzad Ghaffar; Sammer Siddiqui; Iftikhar Salahuddin; Philippe M. Frossard

2004-01-01

169

P. falciparum dihydrofolate reductase and dihydropteroate synthase mutations: epidemiology and role in clinical resistance to antifolates  

Microsoft Academic Search

Plasmodium falciparum resistance to the antifolates has arisen rapidly in Asia and South America, and threatens the usefulness of these drugs in Africa. In vitro resistance to the antifolates is determined by mutations in parasite dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS). The role of DHFR and DHPS mutations in therapeutic failure of antifolate antimalarials is less clear. This review

Christopher V. Plowe; James G. Kublin; Ogobara K. Doumbo

1998-01-01

170

Antifolate resistance due to new and known Plasmodium falciparum dihydrofolate reductase mutations expressed in yeast  

Microsoft Academic Search

Two new dihydrofolate reductase (DHFR) mutations were recently discovered in Plasmodium falciparum samples from an area of Bolivia with high rates of in vivo resistance to pyrimethamine–sulfadoxine: a Cys?Arg point mutation in codon 50 and a five amino acid insertion after codon 30, termed the Bolivia repeat. We used a yeast expression system to screen these new DHFR mutants, as

Joseph F Cortese; Christopher V Plowe

1998-01-01

171

Isolated Renal Vein Thrombosis Associated With MTHFR-1298 and PAI-1 4G Gene Mutations  

Microsoft Academic Search

Isolated renal vein thrombosis is very rare without the presence of nephrotic syndrome. It is more common in the newborns and infants. Whereas major risk factors in adults are the procoagulant states such as protein C or S deficiency, factor V Leiden mutation, primary or secondary antiphospholipid syndrome, severe hypothyroidism, and trauma. Here, we report a case of isolated renal

Hakan Cinemre; Cemil Bilir; Nermin Akdemir

2010-01-01

172

Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene.  

PubMed Central

Smith-Lemli-Opitz syndrome is a frequently occurring autosomal recessive developmental disorder characterized by facial dysmorphisms, mental retardation, and multiple congenital anomalies. Biochemically, the disorder is caused by deficient activity of 7-dehydrocholesterol reductase, which catalyzes the final step in the cholesterol-biosynthesis pathway-that is, the reduction of the Delta7 double bond of 7-dehydrocholesterol to produce cholesterol. We identified a partial transcript coding for human 7-dehydrocholesterol reductase by searching the database of expressed sequence tags with the amino acid sequence for the Arabidopsis thaliana sterol Delta7-reductase and isolated the remaining 5' sequence by the "rapid amplification of cDNA ends" method, or 5'-RACE. The cDNA has an open reading frame of 1,425 bp coding for a polypeptide of 475 amino acids with a calculated molecular weight of 54.5 kD. Heterologous expression of the cDNA in the yeast Saccharomyces cerevisiae confirmed that it codes for 7-dehydrocholesterol reductase. Chromosomal mapping experiments localized the gene to chromosome 11q13. Sequence analysis of fibroblast 7-dehydrocholesterol reductase cDNA from three patients with Smith-Lemli-Opitz syndrome revealed distinct mutations, including a 134-bp insertion and three different point mutations, each of which was heterozygous in cDNA from the respective parents. Our data demonstrate that Smith-Lemli-Opitz syndrome is caused by mutations in the gene coding for 7-dehydrocholesterol reductase.

Waterham, H R; Wijburg, F A; Hennekam, R C; Vreken, P; Poll-The, B T; Dorland, L; Duran, M; Jira, P E; Smeitink, J A; Wevers, R A; Wanders, R J

1998-01-01

173

A common mutation in methylenetetrahydrofolate reductase gene is not a major risk of coronary artery disease or myocardial infarction  

Microsoft Academic Search

A common mutation (C677?T) in methylenetetrahydrofolate (MTHFR) gene, involved in the metabolism of homocysteine, has been suggested to play a role in increasing cardiovascular disease risk. We determined the frequency of C677?T genotypes and alleles in 155 Caucasian patients with angiographically documented coronary artery disease (CAD) and in 155 age and sex matched normal Caucasian individuals. DNA was extracted from

Ramon Brugada; A. J Marian

1997-01-01

174

A Common Variant in Methionine Synthase Reductase Combined with Low Cobalamin (Vitamin B 12) Increases Risk for Spina Bifida  

Microsoft Academic Search

Impairment of folate and cobalamin (vitamin B12) metabolism has been observed in families with neural tube defects (NTDs). Genetic variants of enzymes in the homocysteine remethylation pathway might act as predisposing factors contributing to NTD risk. The first polymorphism linked to increased NTD risk was the 677C?T mutation in methylenetetrahydrofolate reductase (MTHFR). We now report a polymorphism in methionine synthase

Aaron Wilson; Robert Platt; Qing Wu; Daniel Leclerc; Benedicte Christensen; Hong Yang; Roy A. Gravel; Rima Rozen

1999-01-01

175

5,10-Methylenetetrahydrofolate reductase deficiency with progressive polyneuropathy in an infant.  

PubMed

5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency is the most prevalent inborn error of folate metabolism, and has variable clinical manifestations from asymptomatic to severe psychomotor retardation, microcephalus and seizure. In untreated infantile cases, it predominantly affects the central nervous system, which is sometimes fatal. On the other hand, peripheral nerve involvement is uncommon. We present a severe infantile case of MTHFR deficiency that manifested unilateral phrenic nerve palsy with communicating hydrocephalus, developmental delay and died at 11months of age. An enzymatic study confirmed MTHFR deficiency with residual activity of 0.75% of mean control values in cultured fibroblasts. Mutation analysis of the MTHFR gene revealed homozygous, tandem missense mutations c.[446G>T; 447C>T] in exon 3 of the MTHFR gene converting glycine to valine (Gly149Val). In MTHFR deficiency, betaine may improve the symptoms if started immediately after birth by reducing the level of serum homocysteine and increasing that of methionine. Our results show that we should be aware of possible inborn errors of folate metabolism such as MTHFR deficiency, in infants with unexplained developmental delay manifesting rapidly progressive polyneuropathy. PMID:20850942

Tsuji, Megumi; Takagi, Atsushi; Sameshima, Kiyoko; Iai, Mizue; Yamashita, Sumimasa; Shinbo, Hiroko; Furuya, Noritaka; Kurosawa, Kenji; Osaka, Hitoshi

2010-09-20

176

C677T mutation in the 5,10-MTHFR gene and risk of Down syndrome in Italy  

Microsoft Academic Search

The C677T polymorphism of the MTHFR gene has been associated to maternal risk of Down syndrome, due to the detection of an higher prevalence of the T allele among mothers of children with trisomy 21, compared to control mothers. In order to confirm this association, we studied the presence of the C677T in 64 mothers of Down syndrome children and

Liborio Stuppia; Valentina Gatta; Anna Rita Gaspari; Ivana Antonucci; Elisena Morizio; Giuseppe Calabrese; Giandomenico Palka

2002-01-01

177

Methylenetetrahydrofolate Reductase Gene Polymorphisms in Children with Attention Deficit Hyperactivity Disorder  

PubMed Central

Objective: The purpose of this study was to evaluate the relationship between 5,10- methylenetetrahydrofolate reductase (MTHFR) polymorphisms and Attention Deficit Hyperactivity Disorder (ADHD) in a sample of Turkish children. Study Design: MTHFR gene polymorphisms were assessed in 40 patients with ADHD and 30 healty controls. Two mutations in the MTHFR gene were investigated using polymerase chain reactions and restriction fragment length polymorphisms. Results: Although there were no statistically significant differences in genotype distributions of the C677T alleles between the ADHD and the control groups (p=0,678) but the genotypic pattern of the distributions of the A1298C alleles was different between the ADHD patients and the controls (p=0,033). Conclusions: Preliminary data imply a possible relationship between A1298C MTHFR polymorphisms and the ADHD.

Gokcen, Cem; Kocak, Nadir; Pekgor, Ahmet

2011-01-01

178

Association study between methylenetetrahydrofolate reductase gene polymorphisms and Graves' disease.  

PubMed

5,10-Methylenetetrahydrofolate reductase (MTHFR) catalyzes the metabolism of folate and nucleotides, which are essential for DNA synthesis and methylation. It is highly polymorphic, and its variant genotypes result in lower enzymatic activity and higher plasma homocysteine. Previous studies have provided evidence that a high prevalence of MTHFR gene polymorphisms is frequently detected in patients with autoimmune disease, suggesting a novel genetic association with autoimmune disorders. However, the genetic association between MTHFR and Graves' disease (GD), one of the most common autoimmune diseases, has not been studied. Here, we designed a clinic-based case-control study including 199 GD cases and 235 healthy controls to examine the associations between three common MTHFR polymorphisms (i.e., C677T, A1298C, and G1793A) and GD. Surprisingly, logistic regression analysis shows MTHFR 677CT?+?TT genotypes are associated with an approximately 42% reduction in the risk of GD in women (adjusted OR?=?0.58, 95% CI?=?0.3-0.9), compared to the CC genotype, indicating a significant protective effect of 677CT?+?TT genotypes. Our result provides epidemiological evidence that MTHFR mutation (C677T) protects women from GD. The protective effect, possibly obtained by influencing DNA methylation, should be confirmed in a large number of cohorts. PMID:20941748

Mao, Renfang; Fan, Yihui; Zuo, Lulu; Geng, Dongfeng; Meng, Fantao; Zhu, Jing; Li, Qiang; Qiao, Hong; Jin, Yan; Bai, Jing; Fu, Songbin

2010-10-01

179

Folate intake, alcohol consumption, and the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism: influence on prostate cancer risk and interactions  

PubMed Central

Purpose: Folate is essential to DNA methylation and synthesis and may have a complex dualistic role in prostate cancer. Alcohol use may increase risk and epigenetic factors may interact with lifestyle exposures. We aimed to characterize the independent and joint effects of folate intake, alcohol consumption, and the MTHFR C677T gene polymorphism on prostate cancer risk, while accounting for intakes of vitamins B2, B6, B12, methionine, total energy, and confounders. Methods: A case-control study was conducted at Kingston General Hospital of 80 incident primary prostate cancer cases and 334 urology clinic controls, all with normal age-specific PSA levels (to exclude latent prostate cancers). Participants completed a questionnaire on folate and alcohol intakes and potential confounders prior to knowledge of diagnosis, eliminating recall bias, and blood was drawn for MTHFR genotyping. Joint effects of exposures were assessed using unconditional logistic regression and significance of multiplicative and additive interactions using general linear models. Results: Folate, vitamins B2, B6, B12, methionine, and the CT and TT genotypes were not associated with prostate cancer risk. The highest tertile of lifetime alcohol consumption was associated with increased risk (OR = 2.08; 95% CI: 1.12–3.86). Consumption of >5 alcoholic drinks per week was associated with increased prostate cancer risk among men with low folate intake (OR = 2.38; 95% CI: 1.01–5.57), and higher risk among those with the CC MTHFR genotype (OR = 4.43; 95% CI: 1.15–17.05). Increased risk was also apparent for average weekly alcohol consumption when accounting for the multiplicative interaction between folate intake and MTHFR C677T genotype (OR = 3.22; 95% CI: 1.36–7.59). Conclusion: Alcohol consumption is associated with increased prostate cancer risk, and this association is stronger among men with low folate intake, with the CC MTHFR genotype, and when accounting for the joint effect of folate intake and MTHFR C677T genotype.

Kobayashi, Lindsay C.; Limburg, Heather; Miao, Qun; Woolcott, Christy; Bedard, Leanne L.; Massey, Thomas E.; Aronson, Kristan J.

2012-01-01

180

Genomic structure and transcript variants of the human methylenetetrahydrofolate reductase gene.  

PubMed

The human 5,10-methylenetetrahydrofolate reductase (MTHFR) represents a major enzyme in the folate-dependent regulation of methionine and homocysteine concentrations. Different MTHFR mutations lead either to severe homocystinuria as a multisystem disorder or to moderate hyperhomocysteinaemia, which is a common risk factor for disorders ranging from cardiovasculopathy to spina bifida. The N-terminal part of the human MTHFR gene is incompletely characterised. We report the completed genomic structure of this gene including three novel exonic sequences on the basis of a 5'-RACE and a 4.2 kb cloned fragment of human genomic DNA. We demonstrate the existence of four MTHFR transcripts differing in their first exons. The diversity of transcripts is due to alternative transcription initiation and alternative splicing. Three putative polypeptides of 657, 698, and 680 amino acids are encoded. The novel genomic sequence described here includes putative promoter regions as suggested by the presence of regions homologue to binding sites for SP1, AP1, AP2, CAAT or GC boxes. Furthermore, we provide evidence that there are no TATA-box elements to regulate the human MTHFR gene. The results of our study render the full-length characterisation of affected alleles in severe homocystinuria and moderate hyperhomocysteinaemia due to MTHFR deficiency and provide a basis for investigating the regulation of the human MTHFR gene. PMID:10980581

Homberger, A; Linnebank, M; Winter, C; Willenbring, H; Marquardt, T; Harms, E; Koch, H G

2000-09-01

181

MTHFR gene polymorphisms in bladder cancer in the Turkish population.  

PubMed

Bladder cancer is the 9th most common cancer and is responsible for malignancy related death all on the world. Folate and folate related enzyme polymorphisms related to the cancer risk. The methylene tethrahydrofolate reductase (MTHFR) enzyme is folate related and association of bladder cancer and MTHFR gene. Our purpose was to assess the prevalence of MTHFR gene 677 CT and 1298 AC polymorphisms and Bladder cancer in Turkey. We intended that bladder cancer patients and controls and we used the Polymerase Chain Reaction (PCR) and Restriction Fragment Length Polymorphism (RFLP) methods. The MTHFR gene C677T and A1298C polymorphisms were associated with an increased risk of bladder cancer in our population (For the MTHFR gene C677T polymorphism and A1298C polymorphism; p=0.036<0.05; p=0.278>0.05 respectively). Consequently, the MTHFR gene C677T polymorphism augments the risk of bladder cancer in Turkey. PMID:22126575

Izmirli, Muzeyyen; Inandiklioglu, Nihal; Abat, Deniz; Alptekin, Davut; Demirhan, Osman; Tansug, Zuhtu; Bayazit, Yildirim

2011-01-01

182

FREQUENCY OF THE ASN108 AND THR-108 POINT MUTATIONS IN THE DIHYDROFOLATE REDUCTASE GENE INPLASMODIUM FALCIPARUM FROM SOUTHWEST COLOMBIA  

Microsoft Academic Search

Several point mutations in the dihydrofolate reductase (DHFR) gene of Plasmodium falciparumhave been correlated with in vitro anti-folate drug resistance of laboratory and field isolates. Furthermore, two different point mutations that generate amino acid substitutions at the same position of the enzyme have been observed in all the isolates studied to date. These point mutations change a serine (Ser-108) in

LUIS E. GIRALDO; MARTA C. ACOSTA; LUZ A. LABRADA; ANITA PRABA; SONIA MONTENEGRO-JAMES; NANCY G. SARAVIA; DONALD J. KROGSTAD

183

Evaluation of Factor V Leiden, Prothrombin and Methylenetetrahydrofolate Reductase Gene Mutations in Patients with Severe Pregnancy Complications in Northern Finland  

Microsoft Academic Search

Background: Thrombosis in placenta may lead to severe pregnancy complications. Most important inherited thrombophilias are factor V Leiden mutation, prothrombin mutation, and methylenetetrahydrofolate reductase mutation. The aim of our research was to evaluate the prevalence of inherited thrombophilias in severe pregnancy complications and in normal pregnancies. Material and Methods: The study subjects with severe preeclampsia, intrauterine growth restriction, placental abruption

J. Jarvenpaa; M. Pakkila; E.-R. Savolainen; A. Perheentupa; I. Jarvela; M. Ryynanen

2006-01-01

184

A missense mutation in the 3-ketodihydrosphingosine reductase FVT1 as candidate causal mutation for bovine spinal muscular atrophy  

PubMed Central

The bovine form of the autosomal recessive neurodegenerative disease spinal muscular atrophy (SMA) shows striking similarity to the human form of the disease. It has, however, been mapped to a genomic region not harboring the bovine orthologue of the SMN gene, mutation of which causes human SMA. After refinement of the mapping results we analyzed positional and functional candidate genes. One of three candidate genes, FVT1, encoding 3-ketodihydrosphingosine reductase, which catalyzes a crucial step in the glycosphingolipid metabolism, showed a G-to-A missense mutation that changes Ala-175 to Thr. The identified mutation is limited to SMA-affected animals and carriers and always appears in context of the founder haplotype. The Ala variant found in healthy animals showed the expected 3-ketodihydrosphingosine reductase activity in an in vitro enzyme assay. Importantly, the Thr variant found in SMA animals showed no detectable activity. Surprisingly, in an in vivo assay the mutated gene complements the growth defect of a homologous yeast knockout strain as well as the healthy variant. This finding explains the viability of affected newborn calves and the later neuron-specific onset of the disease, which might be due to the high sensitivity of these neurons to changes in housekeeping functions. Taken together, the described mutation in FVT1 is a strong candidate for causality of SMA in cattle. This result provides an animal model for understanding the underlying mechanisms of the development of SMA and will allow efficient selection against the disease in cattle.

Krebs, Stefan; Medugorac, Ivica; Rother, Susanne; Strasser, Katja; Forster, Martin

2007-01-01

185

MTHFR genotypes and breast cancer survival after surgery and chemotherapy: a report from the Shanghai Breast Cancer Study  

Microsoft Academic Search

Summary  Methylenetetrahydrofolate reductase (MTHFR) regulates the intracellular folates pool for DNA synthesis and methylation. Sequence variations in MTHFR (nucleotides 677 (CT) and 1298 (AC)) result in allozymes with decreased activity. The 677TT genotype is associated with increased toxicity of methotrexate and increased clinical response to 5-fluorouracil in treatment of cancers including breast cancer. We evaluated MTHFR genotypes and breast cancer survival

Martha J. Shrubsole; Xiao Ou Shu; Zhi Xian Ruan; Qiuyin Cai; Hui Cai; Qi Niu; Yu-Tang Gao; Wei Zheng

2005-01-01

186

Relations between molecular and biological abnormalities in 11 families from siblings affected with methylenetetrahydrofolate reductase deficiency  

Microsoft Academic Search

Methylenetetrahydrofolate reductase (MTHFR) deficiency is an autosomal recessive disorder resulting in elevated homocysteine levels in plasma and urine. MTHFR catalyses the reduction of methylenetetrahydrofolate to methyltetrahydrofolate, a cofactor for homocysteine remethylation to methionine. MTHFR deficiency may be diagnosed from infancy to adulthood with a broad spectrum of clinical symptoms. A molecular analysis of the MTHFR gene combined with an assessment

Carole Tonetti; Jean-Marie Saudubray; Bernard Echenne; Pierre Landrieu; Stéphane Giraudier; Jacqueline Zittoun

2003-01-01

187

Mutations in the dihydrofolate reductase gene of trimethoprim-resistant isolates of Streptococcus pneumoniae.  

PubMed Central

Streptococcus pneumoniae isolates resistant to several antimicrobial agent classes including trimethoprim-sulfamethoxazole have been reported with increasing frequency throughout the world. The MICs of trimethoprim, sulfamethoxazole, and trimethoprim-sulfamethoxazole (1:19) for 259 clinical isolates from South Africa were determined, and 166 of these 259 (64%) isolates were resistant to trimethoprim-sulfamethoxazole (MICs > or =20 mg/liter). Trimethoprim resistance was found to be more strongly correlated with trimethoprim-sulfamethoxazole resistance (correlation coefficient, 0.744) than was sulfamethoxazole resistance (correlation coefficient, 0.441). The dihydrofolate reductase genes from 11 trimethoprim-resistant (MICs, 64 to 512 microg/ml) clinical isolates of Streptococcus pneumoniae were amplified by PCR, and the nucleotide sequences were determined. Two main groups of mutations to the dihydrofolate reductase gene were found. Both groups shared six amino acid changes (Glu20-Asp, Pro70-Ser, Gln81-His, Asp92-Ala, Ile100-Leu, and Leu135-Phe). The first group included two extra changes (Lys60-Gln and Pro111-Ser), and the second group was characterized by six additional amino acid changes (Glu14-Asp, Ile74-Leu, Gln91-His, Glu94-Asp, Phe147-Ser, and Ala149-Thr). Chromosomal DNA from resistant isolates and cloned PCR products of the genes encoding resistant dihydrofolate reductases were capable of transforming a susceptible strain of S. pneumoniae to trimethoprim resistance. The inhibitor profiles of recombinant dihydrofolate reductase from resistant and susceptible isolates revealed that the dihydrofolate reductase from trimethoprim-resistant isolates was 50-fold more resistant (50% inhibitory doses [ID50s], 3.9 to 7.3 microM) than that from susceptible strains (ID50s, 0.15 microM). Site-directed mutagenesis experiments revealed that one mutation, Ile100-Leu, resulted in a 50-fold increase in the ID50 of trimethoprim. The resistant dihydrofolate reductases were characterized by highly conserved redundant changes in the nucleotide sequence, suggesting that the genes encoding resistant dihydrofolate reductases may have evolved as a result of inter- or intraspecies recombination by transformation.

Adrian, P V; Klugman, K P

1997-01-01

188

PYRIMETHAMINE-SULFADOXINE EFFICACY AND SELECTION FOR MUTATIONS IN PLASMODIUM FALCIPARUMDIHYDROFOLATE REDUCTASE AND DIHYDROPTEROATE SYNTHASE IN MALI  

Microsoft Academic Search

To assess pyrimethamine-sulfadoxine (PS) efficacy in Mali, and the role of mutations in Plasmodium falciparum dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) in in vivo PS resistance, 190 pa- tients with uncomplicated P. falciparum malaria were treated with PS and monitored for 56 days. Mutation-specific polymerase chain reactions and digestion with restriction endonucleases were used to detect DHFR and DHPS

YACOUBA DIOURTE; ABDOULAYE DJIMDE; OGOBARA K. DOUMBO; ISSAKA SAGARA; YOUSSOUF COULIBALY; ALASSANE DICKO; MOUCTAR DIALLO; MAHAMADOU DIAKITE; JOSEPH F. CORTESE; CHRISTOPHER V. PLOWE

189

Loss of heterozygosity at the 5,10-methylenetetrahydrofolate reductase locus in human ovarian carcinomas.  

PubMed Central

The high-affinity folate-binding protein (FBP) is primarily involved in the uptake of the 5-methyltetrahydrofolate, and its expression may be physiologically regulated by the intracellular folate content. The overexpression of FBP on the cell surface of ovarian carcinoma cells may be responsible for an increased folate uptake. We tested the hypothesis of the existence of a defect in the 5, 10-methylenetetrahydrofolate reductase (MTHFR) in ovarian tumours that could cause reduced intracellular regeneration of the 5-methyltetrahydrofolate and induce increased FBP expression. No sequence mutations were found in the MTHFR gene, but allelic deletions of this gene were frequently detected in ovarian tumours (59%). Chromosomal losses appeared to be confined to the 1p36.3 region to which the MTHFR gene maps. Although it cannot be stated that MTHFR is the target gene of the chromosomal loss involving the 1p36.3 region, a correlation between loss of heterozygosity at this locus and decrease in MTHFR activity was shown, suggesting a role of these allelic deletions in generating a biochemical defect in folate metabolism. Further studies are needed to assess further the relationship between MTHFR and FBP overexpression, but the demonstration of the alteration of a key metabolic enzyme of the folate cycle in a subset of human ovarian tumours is in accordance with the hypothesis of an altered folate metabolism in these neoplasias and might be exploited for therapeutic purposes. Images Figure 1 Figure 2

Viel, A.; Dall'Agnese, L.; Simone, F.; Canzonieri, V.; Capozzi, E.; Visentin, M. C.; Valle, R.; Boiocchi, M.

1997-01-01

190

The effect of disease associated point mutations on 5?-reductase (AKR1D1) enzyme function  

PubMed Central

The stereospecific 5?-reduction of ?4-3-ketosterols is very difficult to achieve chemically and introduces a 90° bend between ring A and B of the planar steroid. In mammals, the reaction is catalyzed by steroid 5?-reductase, a member of the aldo-keto reductase (AKR) family. The human enzyme, AKR1D1, plays an essential role in bile-acid biosynthesis since the 5?-configuration is required for the emulsifying properties of bile. Deficient 5?-reductase activity can lead to cholestasis and neo-natal liver failure and is often lethal if it remains untreated. In five patients with 5?-reductase deficiency, sequencing revealed individual, non-synonymous point mutations in the AKR1D1 gene: L106F, P133R, G223E, P198L and R261C. However, mapping these mutations to the AKR1D1 crystal structure failed to reveal any obvious involvement in substrate or cofactor binding or catalytic mechanism, and it remained unclear whether these mutations could be causal for the observed disease. We analyzed the positions of the reported mutations and found that they reside in highly conserved portions of AKR1D1 and hypothesized that they would likely lead to changes in protein folding, and hence enzyme activity. Attempts to purify the mutant enzymes for further characterization by over-expression in E.coli yielded sufficient amounts of only one mutant (P133R). This enzyme exhibited reduced Km and kcat with the bile acid intermediate ?4-cholesten-7?-ol-3-one as substrate reminiscent of uncompetitive inhibition. In addition, P133R displayed no change in cofactor affinity but was more thermolabile as judged by CD-spectroscopy. When all AKR1D1 mutants were expressed in HEK 293 cells, protein expression levels and enzyme activity were dramatically reduced. Furthermore, cycloheximide treatment revealed decreased stability of several of the mutants compared to wild type. Our data show, that all five mutations identified in patients with functional bile acid deficiency strongly affected AKR1D1 enzyme functionality and therefore may be causal for this disease.

Mindnich, Rebekka; Drury, Jason E.; Penning, Trevor M.

2011-01-01

191

Hypercoagulable State and Methylenetetra- hydrofolate Reductase (MTHFR) C677T Mutation in Patients with Beta-Thalassemia Major in Kuwait  

Microsoft Academic Search

Introduction: Patients with thalassemia major often present with a hypercoagulable state, the pathogenesis of which is still not understood. Materials and Methods: This study evaluates the risk factors for hypercoagulability in 50 ?-thalassemia major patients and 50 healthy controls. Fasting total homocysteine, protein C (PC), protein S (PS), antithrombin (AT), activated protein C resistance (APCR) and lupus anticoagulant (LA) were

Nada Y. Mustafa; Rajaa Marouf; Salah Al-Humood; Suad M. Al-Fadhli; Olusegun Mojiminiyi

2010-01-01

192

Novel antifolate resistant mutations of Plasmodium falciparum dihydrofolate reductase selected in Escherichia coli  

Microsoft Academic Search

A simple and effective system has been developed from which a number of Plasmodium falciparum dihydrofolate reductase (pfDHFR) mutants conferring resistance to antifolates were randomly generated and characterized. The system exploited error-prone PCR to generate random mutations in the pfDHFR. Using the synthetic gene encoding for wild-type and quadruple mutant (N51I+C59R+S108N+I164L) pfDHFRs as templates, mutants resistant to pyrimethamine (Pyr), m-Cl

Sudsanguan Chusacultanachai; Pornpan Thiensathit; Bongkoch Tarnchompoo; Worachart Sirawaraporn; Yongyuth Yuthavong

2002-01-01

193

Association of MTHFR gene polymorphisms with breast cancer survival  

Microsoft Academic Search

BACKGROUND: Two functional single nucleotide polymorphisms (SNPs) in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, C677T and A1298C, lead to decreased enzyme activity and affect chemosensitivity of tumor cells. We investigated whether these MTHFR SNPs were associated with breast cancer survival in African-American and Caucasian women. METHODS: African-American (n = 143) and Caucasian (n = 105) women, who had incident breast cancer

Damali N Martin; Brenda J Boersma; Tiffany M Howe; Julie E Goodman; Leah E Mechanic; Stephen J Chanock; Stefan Ambs

2006-01-01

194

Genetic polymorphism of MTHFR G1793A in Chinese populations  

Microsoft Academic Search

5,10-methylenetetrahydrofolate reductase (MTHFR) is an important enzyme in folate metabolism. A novel polymorphic site in\\u000a MTHFR (G1793A) could influence the homocysteine levels and was first described in 2002. Investigations revealed that this allele\\u000a was associated with susceptibility to several cancers, but its distribution around the world was not adequate. To study the\\u000a prevalence of the mutant frequency in Chinese populations,

Renfang Mao; Yihui Fan; Feng Chen; Songbin Fu

2008-01-01

195

Thermolabile MTHFR genotype and retinal vascular occlusive disease  

Microsoft Academic Search

BACKGROUNDRaised levels of total plasma homocysteine (tHcy) are associated with an increased risk of retinal vascular occlusive disease. A thermolabile form of a pivotal enzyme in homocysteine metabolism, methylenetetrahydrofolate reductase (MTHFR), has been associated with vascular occlusive disease and raised tHcy levels. The relation between thermolabile MTHFR genotype, tHcy, and retinal vascular occlusive disease has not been determined.METHODSA retrospective case-control

M Cahill; M Karabatzaki; C Donoghue; R Meleady; L A Mynett-Johnson; D Mooney; I M Graham; A S Whitehead; D C Shields

2001-01-01

196

Smith-Lemli-Opitz syndrome: evidence of T93M as a common mutation of ?7-sterol reductase in Italy and report of three novel mutations  

Microsoft Academic Search

The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder of cholesterol biosynthesis characterised by facial dysmorphisms, mental retardation and multiple congenital anomalies. SLOS is caused by mutations of the human ?7-sterol reductase (DHCR7) gene and, so far, 19 different mutations have been described. Among these, mutations impairing the activity of the C-terminus appear to be the most severe. Here we

D De Brasi; T Esposito; M Rossi; G Parenti; MP Sperandeo; A Zuppaldi; T Bardaro; MA Ambruzzi; L Zelante; A Ciccodicola; G Sebastio; M D'Urso; G Andria

1999-01-01

197

Association of the MTHFR A1298C Variant with Unexplained Severe Male Infertility  

Microsoft Academic Search

The methylenetetrahydrofolate reductase (MTHFR) gene is one of the main regulatory enzymes involved in folate metabolism, DNA synthesis and remethylation reactions. The influence of MTHFR variants on male infertility is not completely understood. The objective of this study was to analyze the distribution of the MTHFR C677T and A1298C variants using PCR-Restriction Fragment Length Polymorphism (RFLP) in a case group

Abdelmajid Eloualid; Omar Abidi; Majida Charif; Brahim El houate; Houda Benrahma; Noureddine Louanjli; Elbakkay Chadli; Maria Ajjemami; Abdelhamid Barakat; Anu Bashamboo; Ken McElreavey; Houria Rhaissi; Hassan Rouba

2012-01-01

198

Influence of maternal MTHFR A1298C polymorphism on the risk in offspring of schizophrenia  

Microsoft Academic Search

Several lines of evidence have suggested that two functional methylenetetrahydrofolate reductase gene (MTHFR) polymorphisms, C677T and A1298C, may be implicated in the etiology of schizophrenia. We examined these MTHFR polymorphisms in 111 families, composed of a patient and their parents, as well as 143 mothers of patients with schizophrenia and 235 age-matched mothers who had healthy children. The maternal MTHFR

Chen Zhang; Bin Xie; Yiru Fang; Wenhong Cheng; Yasong Du; Dongxiang Wang; Shunying Yu

2010-01-01

199

Prevalence of MTHFR gene polymorphisms (C677T and A1298C) among Tamilians  

Microsoft Academic Search

We have investigated the incidence of the C677T and A1298C methylene tetrahydrofolate reductase (MTHFR) gene single nucleotide polymorphisms (SNPs) in the South Indian Tamil Nadu population with a total number of 72 individuals. The MTHFR genotyping was performed using the polymerase chain reaction followed by restriction enzyme analysis. Homozygosity for the MTHFR A1298C SNP was detected in 15.3% (11\\/72) of

T. Angeline; Nirmala Jeyaraj; Selena Granito; Gregory J. Tsongalis

2004-01-01

200

Mutation in Pyrroline-5-Carboxylate Reductase 1 Gene in Families with Cutis Laxa Type 2  

PubMed Central

Autosomal-recessive cutis laxa type 2 (ARCL2) is a multisystem disorder characterized by the appearance of premature aging, wrinkled and lax skin, joint laxity, and a general developmental delay. Cutis laxa includes a family of clinically overlapping conditions with confusing nomenclature, generally requiring molecular analyses for definitive diagnosis. Six genes are currently known to mutate to yield one of these related conditions. We ascertained a cohort of typical ARCL2 patients from a subpopulation isolate within eastern Canada. Homozygosity mapping with high-density SNP genotyping excluded all six known genes, and instead identified a single homozygous region near the telomere of chromosome 17, shared identically by state by all genotyped affected individuals from the families. A putative pathogenic variant was identified by direct DNA sequencing of genes within the region. The single nucleotide change leads to a missense mutation adjacent to a splice junction in the gene encoding pyrroline-5-carboxylate reductase 1 (PYCR1). Bioinformatic analysis predicted a pathogenic effect of the variant on splice donor site function. Skipping of the associated exon was confirmed in RNA from blood lymphocytes of affected homozygotes and heterozygous mutation carriers. Exon skipping leads to deletion of the reductase functional domain-coding region and an obligatory downstream frameshift. PYCR1 plays a critical role in proline biosynthesis. Pathogenicity of the genetic variant in PYCR1 is likely, given that a similar clinical phenotype has been documented for mutation carriers of another proline biosynthetic enzyme, pyrroline-5-carboxylate synthase. Our results support a significant role for proline in normal development.

Guernsey, Duane L.; Jiang, Haiyan; Evans, Susan C.; Ferguson, Meghan; Matsuoka, Makoto; Nightingale, Mathew; Rideout, Andrea L.; Provost, Sylvie; Bedard, Karen; Orr, Andrew; Dube, Marie-Pierre; Ludman, Mark; Samuels, Mark E.

2009-01-01

201

Alterations in intracellular deoxyribonucleotide levels of mutationally altered ribonucleotide reductases in Escherichia coli.  

PubMed Central

Four recombinant plasmid clones (pPS305, pPS308, pPS317, and pPS319) coding for Escherichia coli ribonucleotide reductase have been characterized in vivo and in vitro. Each clone carried a different missense mutation affecting the B1 subunit. Measurements were made of deoxyribonucleoside triphosphate pools. Cells carrying the wild-type plasmid, pPS2, overproduced ribonucleotide reductase 10 to 20 times. As a consequence of this elevated enzyme level, the deoxyribonucleotide pools were approximately three times higher. All four mutant clones showed disturbed deoxyribonucleotide pools. The in vitro studies involved chromatography on affinity media, measurements of enzyme activity and allosteric regulation with a variety of substrates and effector molecules, and direct photoaffinity labeling in the presence of dTTP. Clones pPS305 and pPS308 were shown to code for catalytically defective enzymes, whereas clones pPS317 and pPS319 were shown to code for allosterically altered enzymes. The characterized missense mutations can thus be localized to areas involved in regulation of the substrate specificity or to the active site of protein B1. The alteration of the deoxyribonucleotide pools found in cells containing the allosterically defective clones pPS317 and pPS319 clearly demonstrated in vivo significance for the allosteric control of protein B1 in E. coli cells.

Platz, A; Karlsson, M; Hahne, S; Eriksson, S; Sjoberg, B M

1985-01-01

202

MTHFR C677T and A1298C variant genotypes and the risk of microsatellite instability among Iranian colorectal cancer patients  

Microsoft Academic Search

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the folate metabolic pathway. We aimed to test the hypothesis that C677T and A1298C variants of MTHFR predispose to microsatellite instable (MSI) colorectal cancer. We determined MTHFR genotypes in 175 sporadic colorectal cancer patients and a total of 231 normal controls in Shiraz, Southern Iran. Among the genotypes found in our samples,

Fakhraddin Naghibalhossaini; Pooneh Mokarram; Islam Khalili; Mohammad Vasei; Seyed Vahid Hosseini; Hassan Ashktorab; Mozhgan Rasti; Kourosh Abdollahi

2010-01-01

203

Aerobic inactivation of fumarate reductase from Escherichia coli by mutation of the [3Fe-4S]-quinone binding domain.  

PubMed Central

Fumarate reductase from Escherichia coli functions both as an anaerobic fumarate reductase and as an aerobic succinate dehydrogenase. A site-directed mutation of E. coli fumarate reductase in which FrdB Pro-159 was replaced with a glutamine or histidine residue was constructed and overexpressed in a strain of E. coli lacking a functional copy of the fumarate reductase or succinate dehydrogenase complex. The consequences of these mutations on bacterial growth, assembly of the enzyme complex, and enzymatic activity were investigated. Both mutations were found to have no effect on anaerobic bacterial growth or on the ability of the enzyme to reduce fumarate compared with the wild-type enzyme. The FrdB Pro-159-to-histidine substitution was normal in its ability to oxidize succinate. In contrast, however, the FrdB Pro-159-to-Gln substitution was found to inhibit aerobic growth of E. coli under conditions requiring a functional succinate dehydrogenase, and furthermore, the aerobic activity of the enzyme was severely inhibited upon incubation in the presence of its substrate, succinate. This inactivation could be prevented by incubating the mutant enzyme complex in an anaerobic environment, separating the catalytic subunits of the fumarate reductase complex from their membrane anchors, or blocking the transfer of electrons from the enzyme to quinones. The results of these studies suggest that the succinate-induced inactivation occurs by the production of hydroxyl radicals generated by a Fenton-type reaction following introduction of this mutation into the [3Fe-4S] binding domain. Additional evidence shows that the substrate-induced inactivation requires quinones, which are the membrane-bound electron acceptors and donors for the succinate dehydrogenase and fumarate reductase activities. These data suggest that the [3Fe-4S] cluster is intimately associated with one of the quinone binding sites found n fumarate reductase and succinate dehydrogenase.

Cecchini, G; Sices, H; Schroder, I; Gunsalus, R P

1995-01-01

204

A Possible Genetic Link between MTHFR Genotype and Smoking Behavior  

PubMed Central

Background Hyperhomocysteinemia is an independent risk factor for stroke and other vascular events. The variant methylenetetrahydrofolate reductase (MTHFR) C677T is associated with elevated homocysteine levels, cardiovascular disease and stroke, which supports a causal relationship between hyperhomocysteinemia and vascular disease. However, MTHFR variants have also been reported to be associated with smoking behavior, which could be an important confounder. Methodology/Principal Findings We analyzed the MTHFR variants C677T and A1298C in two independent samples of 525 and 535 individuals, respectively. 21% of the non-smokers, but only 12% of the smokers were homozygous carriers of both MTHFR wildtype alleles, i.e. 677CC and 1298AA (Chi2?=?15.8; p<0.001; binary regression). Plasma homocysteine levels were higher in smokers (13.9±4.1 µmol/L) than in non-smokers (12.6±4.0 µmol/L; F?=?11.4; p?=?0.001; ANOVA). Smoking MTHFR 677TT individuals had the highest plasma homocysteine levels (16.2±5.2 µmol/L), non-smoking 677CC individuals had the lowest (12.2±13.6 µmol/L). Conclusions/Significance In our study samples, MTHFR variants and smoking behaviour were associated with homocysteine plasma levels. In addition, the MTHFR variants were associated with smoking behaviour. Such an association may be a relevant confounder between MTHFR variants, homocysteine plasma levels and vascular diseases.

Linnebank, Michael; Moskau, Susanna; Semmler, Alexander; Hoefgen, Barbara; Bopp, Gisela; Kallweit, Ulf; Maier, Wolfgang; Schutz, Christian G.; Wullner, Ullrich

2012-01-01

205

Cerebral sinus venous thrombosis in a subject with thyrotoxicosis and MTHFR gene polymorphism.  

PubMed

We report a case of cerebral venous thrombosis (CVT) due to tyrotoxicosis in a patient with methylenetetrahydro-folate-reductase (MTHFR) gene polymorphism C677T, (genotype 677TT), in which discontinuation of intravenous heparin was followed by clinical and radiological worsening despite warfarin treatment. We discuss the relationship between CVT, MTHFR hyperthiroidism and anticoagulant therapy. PMID:18941937

Strada, Laura; Gandolfo, Carlo; Del Sette, Massimo

2008-10-21

206

Biological and clinical implications of the MTHFR C677T polymorphism  

Microsoft Academic Search

The enzyme methylenetetrahydrofolate reductase (MTHFR) directs folate species either to DNA synthesis or to homocysteine (Hcy) remethylation. The common MTHFR C677T polymorphism affects the activity of the enzyme and hence folate distribution. Under conditions of impaired folate status, the homozygous TT genotype has been regarded as harmful because it is associated with a high concentration of plasma total Hcy, increased

Per Magne Ueland; Steinar Hustad; Jřrn Schneede; Helga Refsum; Stein Emil Vollset

2001-01-01

207

A1298C polymorphism in the MTHFR gene predisposes to cardiovascular risk in rheumatoid arthritis  

Microsoft Academic Search

INTRODUCTION: We determined the contribution of the methylene tetrahydrofolate reductase (MTHFR) 677 C>T and 1298 A>C gene polymorphisms to the susceptibility to rheumatoid arthritis (RA). We also assessed whether these two MTHFR gene polymorphisms may be implicated in the development of cardiovascular (CV) events and subclinical atherosclerosis manifested by the presence of endothelial dysfunction, in a series of Spanish patients

Rogelio Palomino-Morales; Carlos Gonzalez-Juanatey; Tomas R Vazquez-Rodriguez; Luis Rodriguez; Jose A Miranda-Filloy; Benjamin Fernandez-Gutierrez; Javier Llorca; Javier Martin; Miguel A Gonzalez-Gay

2010-01-01

208

Effect Of Metylenetetrahydrofolate Reductase 677 CT, 1298 AC, and 1317 TC on Factor V 1691 Mutation in Turkish Deep Vein Thrombosis Patients  

Microsoft Academic Search

Possible effect of three common mutations in (MTHFR 677 C-T; 1317 T-C; 1298 C-A) and FV 1691 G-A mutation was studied in Turkish patients with thrombosis and compared with normal controls. The case–control study included 68 patients with the diagnosis of deep vein thrombosis and 66 controls, consecutively selected among subjects without personal and familial history of atherothrombosis. Patients with

Nejat Akar; Ece Akar; Remin Akçay; Ferit Avcu; Atila Yalcin; Sukru Cin

2000-01-01

209

Molecular characterization of five patients with homocystinuria due to severe methylenetetrahydrofolate reductase deficiency.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) plays a major role in folate metabolism. Disturbed function of the enzyme results in hyperhomocysteinemia and causes severe vascular and neurological disorders and developmental delay. Five patients suspected of having non-classical homocystinuria due to MTHFR deficiency were examined with respect to their symptoms, MTHFR enzyme activity and genotypes of the MTHFR gene. All patients presented symptoms of severe central nervous system disease. Two patients died, at the ages of 15 months and 14 years. One patient is currently 32 years old, and is being treated with betaine and folinic acid. The other two patients, with an early diagnosis and a severe course of the disease, are currently improving under treatment. MTHFR enzyme activity in the fibroblasts of four of the patients was practically undetectable. We found four novel mutations, three of which were missense changes c.664G> T (p.V218L), c.1316T> C (p.F435S) and c.1733T> G (p.V574G), and the fourth was the 1-bp deletion c.1780delC (p.L590CfsX72). We also found the previously reported nonsense mutation c.1420G> T (p.E470X). All the patients were homozygous. Molecular modelling of the double mutant allele (p.V218L; p.A222V) revealed that affinity for FAD was not affected in this mutant. For the p.E470X mutation, the evidence pointed to nonsense-mediated mRNA decay. In general, genotype-phenotype analysis predicts milder outcomes for patients with missense changes than for those in which mutations led to severe alterations of the MTHFR protein. PMID:20236116

Urreizti, R; Moya-García, A A; Pino-Ángeles, A; Cozar, M; Langkilde, A; Fanhoe, U; Esteves, C; Arribas, J; Vilaseca, M A; Pérez-Dueńas, B; Pineda, M; González, V; Artuch, R; Baldellou, A; Vilarinho, L; Fowler, B; Ribes, A; Sánchez-Jiménez, F; Grinberg, D; Balcells, S

2010-11-01

210

Study of MTHFR and MS polymorphisms as risk factors for NTD in the Italian population.  

PubMed

Homozygosity for the C677T mutation in the methylenetetrahydrofolate reductase ( MTHFR) gene is a risk factor for neural tube defects (NTDs) in many populations, including Italians. Another common mutation on the MTHFR gene, A1298C, has also been described as a risk mutation. Furthermore, several studies have suggested that a defective methionine synthase ( MS) enzyme could be a critical defect in folate-related NTDs. An A-to-G transition at bp 2756 on the MS gene has also been reported. In this case-control study, we studied the frequencies of these two polymorphisms in 203 Italian probands with non-syndromic NTDs: 98 mothers, 67 fathers, and 210 control individuals. Although the A1298C polymorphism is common in the Italian population (0.25), the allelic frequency was significantly higher among NTD cases and their parents. Heterozygous patients and mothers have an odds ratio (OR) of 1.98 and 2.11, respectively. The risk associated with the 1298CC genotype was higher for cases (OR = 3.67), for fathers (OR = 3.28), and, above all, for mothers (OR = 6.23). The prevalence of the A2756G polymorphism of the MS gene was determined (0.15). No increased prevalence of the mutated G allele was found in NTD families. This study shows that the MTHFRA1298C polymorphism is a genetic determinant for NTD risk in Italy. No association between the MSA2756G and NTD susceptibility was found. PMID:12111380

De Marco, Patrizia; Calevo, Maria Grazia; Moroni, Anna; Arata, Lorenza; Merello, Elisa; Finnell, Richard H; Zhu, Huiping; Andreussi, Luciano; Cama, Armando; Capra, Valeria

2002-01-01

211

MTHFR polymorphisms in gastric cancer and in first-degree relatives of patients with gastric cancer.  

PubMed

Two common mutations, 677 C-->T and a1298 A-->C, in the methylenetetrahydrofolate reductase gene (MTHFR) reduce the activity of MTHFR and folate metabolism. Familial aggregation in a variable but significant proportion of gastric cancer (GC) cases suggests the importance of genetic predisposition in determining risk. In this study, we evaluate MTHFR polymorphisms in 57 patients with a diagnosis of GC, in 37 with a history of GC in first-degree relatives (GC-relatives), and in 454 blood donors. Helicobacter pylori (HP) infection was also determined. An increased risk was found for 677TT in GC patients with respect to blood donors (odds ratio (OR) = 1.98), and statistical significance was sustained when we compared sex-age-matched GC patients and donors (OR = 2.37). The 677TT genotype association with GC was found in women (OR = 3.10), while a reduction in the 667C allele frequency was present in both the sex. No statistically significant association was detected when 677-1298 genotype was stratified by sex and age. Men of GC-relatives showed a higher 1298C allele frequency than donors (OR = 4.38). Between GC and GC-relatives, HP infection frequency was similar. In conclusion, overall findings support the hypothesis that folate plays a role in GC risk. GC-relatives evidence a similar 677TT frequency to that found in the general population. PMID:20237899

De Re, Valli; Cannizzaro, R; Canzonieri, V; Cecchin, E; Caggiari, L; De Mattia, E; Pratesi, C; De Paoli, P; Toffoli, G

2009-12-18

212

Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition  

Microsoft Academic Search

Hyperhomocysteinemia, a risk factor for cardiovascular disease, is caused by nutritional and\\/or genetic disruptions in homocysteine metabolism. The most common genetic cause of hyperhomocysteinemia is the 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene. This variant, with mild enzymatic deficiency, is associated with an increased risk for neural tube defects and pregnancy complications and with a decreased risk for colon

Zhoutao Chen; A C Karaplis; Susan L. Ackerman; Igor P. Pogribny; Stepan Melnyk; Cacan S Lussier; Moy Fong Chen; A Pai; S W John; R S Smith; T Bottiglieri; P Bagley; J Selhub; M A Rudnicki; S J James; R Rozen

2001-01-01

213

Hypercoagulable state mutation analysis in white patients with early first-trimester recurrent pregnancy loss  

Microsoft Academic Search

Objective: Antiphospholipid antibodies (APA) and other coagulation abnormalities have been associated with an increased risk of venous, arterial, and placental thrombosis and recurrent pregnancy loss (RPL). Factor V Leiden (a point mutation [1691G?A] in the factor V gene), the prothrombin 20210G?A mutation, and homozygosity for a common polymorphism in the methylene tetrahydrofolate reductase (MTHFR) gene (677C?T) have been associated with

William H Kutteh; Vicki M Park; Steven R Deitcher

1999-01-01

214

Polymorphisms in the CBS gene and homocysteine, folate and vitamin B12 levels: association with polymorphisms in the MTHFR and MTRR genes in Brazilian children.  

PubMed

Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR) and cystathionine beta-synthase (CBS) genes, involved in the intracellular metabolism of homocysteine (Hcy), can result in hyperhomocysteinemia. The objective of this study was to evaluate prevalence estimates of CBS T833C, G919A and the insertion of 68-bp (844ins68) polymorphisms and their correlation with Hcy, folate and B(12) in 220 children previously genotyped for MTHFR C677T, A1298C, and MTRR A66G. The prevalence of heterozygote children for 844ins68 was 19.5%. The T833C CBS mutation was identified in association with 844ins68 in all the carriers of the insertion. Genotyping for CBS G919A mutation showed that all the children presented the GG genotype. Analysis of Hcy, B(12) and folate, according to the combination of the different genotypes of the C677T and A1298C MTHFR, A66G MTRR, and 844ins68 CBS showed that the 677TT/1298AA/68WW genotype is associated with an increase in Hcy, when compared to the 677CC/1298AC/68WW (P = 0.033) and the 677CT/1298AA/68WW genotypes (P = 0.034). Since B(12) and folate were not different between these groups, a genetic interaction between diverse polymorphisms probably influences Hcy. Our results emphasize the role of genetic interactions in Hcy levels. PMID:18792976

Aléssio, Ana C M; Siqueira, Lúcia H; Bydlowski, Sérgio P; Höehr, Nelci F; Annichino-Bizzacchi, Joyce M

2008-10-15

215

Cortisone-reductase deficiency associated with heterozygous mutations in 11?-hydroxysteroid dehydrogenase type 1  

PubMed Central

In peripheral target tissues, levels of active glucocorticoid hormones are controlled by 11?-hydroxysteroid dehydrogenase type 1 (11?-HSD1), a dimeric enzyme that catalyzes the reduction of cortisone to cortisol within the endoplasmic reticulum. Loss of this activity results in a disorder termed cortisone reductase deficiency (CRD), typified by increased cortisol clearance and androgen excess. To date, only mutations in H6PD, which encodes an enzyme supplying cofactor for the reaction, have been identified as the cause of disease. Here we examined the HSD11B1 gene in two cases presenting with biochemical features indicative of a milder form of CRD in whom the H6PD gene was normal. Novel heterozygous mutations (R137C or K187N) were found in the coding sequence of HSD11B1. The R137C mutation disrupts salt bridges at the subunit interface of the 11?-HSD1 dimer, whereas K187N affects a key active site residue. On expression of the mutants in bacterial and mammalian cells, activity was either abolished (K187N) or greatly reduced (R137C). Expression of either mutant in a bacterial system greatly reduced the yield of soluble protein, suggesting that both mutations interfere with subunit folding or dimer assembly. Simultaneous expression of mutant and WT 11?-HSD1 in bacterial or mammalian cells, to simulate the heterozygous condition, indicated a marked suppressive effect of the mutants on both the yield and activity of 11?-HSD1 dimers. Thus, these heterozygous mutations in the HSD11B1 gene have a dominant negative effect on the formation of functional dimers and explain the genetic cause of CRD in these patients.

Lawson, Alexander J.; Walker, Elizabeth A.; Lavery, Gareth G.; Bujalska, Iwona J.; Hughes, Beverly; Arlt, Wiebke; Stewart, Paul M.; Ride, Jonathan P.

2011-01-01

216

Hyperhomocysteinemia and of Methylenetetrahydrofolate Reductase (C677T) Genetic Polymorphism in Patients with Deep Vein Thrombosis  

PubMed Central

Aim: To determine the concentration of total plasma homocysteine (tHcy) as well as different genotypes of methylenetetrahydrofolate reductase MTHFR (C677T) in healthy subjects and patients with deep vein thrombosis (DVT). Material and methods: The investigation comprised a total of 160 subjects divided in two main groups: 80 healthy subjects (control group) and 80 patients with deep vein thrombosis. Concentration of tHcy was determined by spectrophotometric cyclic enzymatic method and mutation of MTHFR (C677T) gene was examined by polymerase chain reaction according to Schneider. Results: The results obtained for plasma tHcy in the control group were 11.62±3.43 ?mol/L, while tHcy level was significantly higher in patients with deep vein thrombosis as compared to the control group, 15.19±3.63 ?mol/L (?<0.001). The analysis of the results has shown that MTHFR (C677T) genetic polymorphism was responsible for mild to moderate hyperhomocysteinemia in the majority of subjects. Conclusion: The level of tHcy in the examined patients was significantly higher in comparison with the control group. Multiple regression analysis has shown that tHcy level in CT and TT genotypes of MTHFR (C677T) was statistically higher in comparison with CC genotype of MTHFR (C677T) in both, the control group and the DVT patients.

Brezovska-Kavrakova, Julijana; Krstevska, Marija; Bosilkova, Gordana; Alabakovska, Sonja; Panov, Saso; Orovchanec, Nikola

2013-01-01

217

Methylenetetrahydrofolate reductase polymorphisms increase risk of esophageal squamous cell carcinoma in a Chinese population.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) plays a central role in folate metabolism that affects DNA methylation and synthesis. Because germ-line mutations at nucleotides 677 (C-->T) and 1298 (A-->C) in the MTHFR gene cause diminished enzyme activity, and aberrant DNA methylation is oncogenic, we examined the relationship between these two MTHFR polymorphisms and susceptibility to esophageal squamous cell carcinoma (ESCC) in 240 ESCC cases and 360 age- and sex-matched controls in northern CHINA: We found that the allele frequency of MTHFR 677T was significantly higher among cases than among controls (63% versus 41%, P < 0.001). Subjects with the 677TT genotype had a more than 6-fold increased risk of developing ESCC [adjusted odds ratio (OR), 6.18; 95% confidence interval (CI), 3.32-11.51] compared with those who had the 677CC genotype. Furthermore, the elevated ESCC risk associated with the 677 polymorphism was in an allele-dose relationship (trend test, P = 0.0001) with ORs of 1.00, 3.14 (95% CI, 1.94-5.08), and 6.18 (95% CI, 3.32-11.51) for the CC, CT, and TT genotype, respectively, after adjustment for age, sex, smoking status, and the MTHFR 1298 polymorphism. The allele frequency for the MTHFR 1298C was 14% among cases and 17% among controls. The 1298CC genotype was extremely rare in both controls (1.4%) and cases (2.9%) and was also associated with an elevated risk of ESCC (adjusted OR, 4.43; 95% CI, 1.23-16.02) compared with the 1298AA genotype, whereas the 1298AC genotype had no effect on the risk of ESCC. Thus, our findings support the hypothesis that genetic polymorphisms in the MTHFR gene may contribute to susceptibility to carcinogenesis of the esophagus in the at-risk Chinese population. PMID:11309278

Song, C; Xing, D; Tan, W; Wei, Q; Lin, D

2001-04-15

218

Genetic Polymorphisms in the Methylenetetrahydrofolate Reductase and Thymidylate Synthase Genes and Risk of Hepatocellular Carcinoma  

PubMed Central

Methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TYMS) are known to play a role in DNA methylation, synthesis, and repair. The genetic mutations in MTHFR and TYMS genes may have influences on their respective enzyme activities. Data on the association studies of the MTHFR and TYMS genetic polymorphisms and risk of hepatocellular carcinoma (HCC) are sparse. MTHFR and TYMS genotypes were determined on 365 HCC cases and 457 healthy control subjects among Hispanic and non-Hispanic whites and African-Americans in Los Angeles County, California, and among Chinese in the city of Nanning, Guangxi, China. Relative to the high-activity genotype, each low-activity genotype of MTHFR was associated with a statistically nonsignificant 30% to 50% reduction in risk of HCC. Relative to the TYMS3?UTR +6/+6 genotype, individuals with 1 or 2 copies of the deletion allele had a statistically significant 50% reduction in risk of HCC. When we examined HCC risk by the total number of mutant alleles in the 3 polymorphic loci of MTHFR/TYMS (range, 0-4), there was a monotonic decrease in risk with increasing number of mutant alleles (P for trend = 0.003). Individuals possessing the maximum number of mutant alleles (i.e., 4) had an odds ratio of 0.46 (95% confidence interval = 0.23-0.93) for HCC compared with those with no or only 1 mutant allele. Conclusion This study supports the hypothesis that reduced MTHFR activity and enhanced TYMS activity, both of which are essential elements in minimizing uracil misincorporation into DNA, may protect against the development of HCC.

Yuan, Jian-Min; Lu, Shelly C.; Van Den Berg, David; Govindarajan, Sugantha; Zhang, Zhen-Quan; Mato, Jose M.; Yu, Mimi C.

2008-01-01

219

Two novel mutations of SRD5A2 gene in Indonesian siblings with clinical 5-alpha-reductase deficiency.  

PubMed

Steroid 5-alpha-reductase 2 deficiency is an autosomal recessive disorder with clinical spectrum ranges from a male phenotype with hypospadia to a female phenotype with normal wolffian structures. Over 50 different mutations of SRD5A2 gene has been described in affected patients and several mutations were detected in specific populations. DNAs of two 46,XY DSD Indonesian siblings, aged 13 and 18 years old, with clinically suspected of 5-alpha-reductase deficiency and their mother were analysed for molecular defects of SRD5A2 gene. Different from other reports, in our series three mutations were found in each patient. Two novel mutations were detected in these patients and their mother, which are p.Gly34fs and c.699-1G>T. The other mutation detected was c.680G>A or p.Arg227Gln, which commonly described in Far East Asian population. Whether the p.Arg227Gln mutation is considered a polymorphism or a mutation in Indonesian population warrants further study. PMID:21714467

Marzuki, Nanis S; Suciati, Lita Putri; Dewi, Mewahyu; Tridjaja, Bambang

2010-12-01

220

MTHFR A1298C polymorphism is associated with cardiovascular risk in end stage renal disease in North Indians  

Microsoft Academic Search

The methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism has been shown to be associated with cardiovascular\\u000a disease and in patients with end-stage renal disease (ESRD). However, the relationship between MTHFR polymorphisms and cardiovascular\\u000a disease (CVD) in patients on hemodialysis has not been examined. The aim of this study was to assess the association of polymorphisms\\u000a of MTHFR gene with homocysteine (Hcy)

Aruna Poduri; Debabrata Mukherjee; Kamal Sud; Harbir Singh Kohli; Vinay Sakhuja; Madhu Khullar

2008-01-01

221

Analysis of MTHFR polymorphisms and P16 methylation and their correlation with clinical–biological features of multiple myeloma  

Microsoft Academic Search

Background  Low folate intake and changes in folate metabolism due to polymorphisms in the methylentetrahydrofolate reductase (MTHFR) gene have been associated with myelomagenesis. However, controversial data have been published regarding a protective role of variant alleles of MTHFR on MM.Patients and methods  To investigate the influence of two common polymorphisms of MTHFR C677T and A1298C on the risk of multiple myeloma (MM),

Patrizia Chiusolo; Giuliana Farina; Rossana Putzulu; Giovanni Reddiconto; Alessia Fiorini; Valerio De Stefano; Elena Rossi; Mariangela Palladino; Giuseppe Leone; Simona Sica

2006-01-01

222

Dietary intake of folate and co-factors in folate metabolism, MTHFR polymorphisms, and reduced rectal cancer  

Microsoft Academic Search

Little is known about the contribution of polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR) and the folate metabolism pathway in rectal cancer alone. Data were from participants in a case–control study conducted\\u000a in Northern California and Utah (751 cases and 979 controls). We examined independent associations and interactions of folate,\\u000a B vitamins, methionine, alcohol, and MTHFR polymorphisms (MTHFR C677T and

Maureen A. Murtaugh; Karen Curtin; Carol Sweeney; Roger K. Wolff; Richard Holubkov; Bette J. Caan; Martha L. Slattery

2007-01-01

223

The association of p53 mutations and p53 codon 72, Her 2 codon 655 and MTHFR C677T polymorphisms with breast cancer in Northern Greece  

Microsoft Academic Search

The aim of this study was to explore a possible association between p53 codon 72, Her 2 codon 655 and MTHFR C677T polymorphisms and breast cancer in Northern Greece. We examined 42 women with breast cancer and 51 controls. A total of 42 women with breast cancer as well as healthy controls were investigated and results showed that p53 codon

Theodora G. Kalemi; Alexandros F. Lambropoulos; Maria Gueorguiev; Sofia Chrisafi; Konstantinos T. Papazisis; Alexandros Kotsis

2005-01-01

224

Characterization of Disease-related 5?-Reductase (AKR1D1) Mutations Reveals Their Potential to Cause Bile Acid Deficiency*  

PubMed Central

Bile acid deficiency is a serious syndrome in newborns that can result in death if untreated. 5?-Reductase deficiency is one form of bile acid deficiency and is characterized by dramatically decreased levels of physiologically active 5?-reduced bile acids. AKR1D1 (aldo-keto reductase 1D1) is the only known human enzyme that stereo-specifically reduces the ?4 double bond in 3-keto steroids and sterols to yield the 5?-hydrogenated product. Analysis of the AKR1D1 gene in five patients with 5?-reductase deficiency revealed five different mutations resulting in an amino acid substitution in the protein. To investigate a causal role for these observed point mutations in AKR1D1 in 5?-reductase deficiency, we characterized their effect on enzymatic properties. Attempts to purify mutant enzymes by overexpression in Escherichia coli only yielded sufficient amounts of the P133R mutant for further characterization. This enzyme displayed a highly reduced Km and Vmax reminiscent of uncompetitive kinetics with 4-cholesten-7?-ol-3-one as substrate. In addition, this mutant displayed no change in cofactor affinity but was more thermolabile in the absence of NADPH as judged by CD spectroscopy. All mutants were compared following expression in HEK 293 cells. Although these enzymes were equally expressed based on mRNA levels, protein expression and functional activity were dramatically reduced. Cycloheximide treatment also revealed that several of the expressed mutants were less stable. Our findings show that the reported mutations in AKR1D1 in patients with 5?-reductase lead to significantly decreased levels of active enzyme and could be causal in the development of bile acid deficiency syndrome.

Drury, Jason E.; Mindnich, Rebekka; Penning, Trevor M.

2010-01-01

225

Allelic variations in 5, 10-methylenetetrahydrofolate reductase gene and susceptibility to cervical cancer in Indian women.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) gene located on chromosome 1p36.3 catalyses the conversion of 5,10-methylenetetrahydrofolate to 5,methyltetrahydrofolate, the major methyl donor for the conversion of homocysteine to methionine. Two common polymorphisms in the MTHFR gene have been identified, 677C>T in exon 4, leading to substitution of alanine by valine and 1298A>C in exon 7 which leads to the replacement of glutamic acid by alanine resulting into reduced enzyme activity. The potential influence of MTHFR activity on DNA methylation and on the availability of uridylates and thymidylates for DNA synthesis and repair makes MTHFR an attractive candidate for cancer predisposing gene. In order to elucidate the role of MTHFR polymorphism in cervical cancer, both the exons for 677C>T and 1298A>C mutations were analyzed among 219 females, including 77 females with normal cervical cytology, 80 with cervical dysplasia and 62 with squamous cell carcinoma of uterine cervix. Females with mutant allele at 677 position (CT/TT genotypes) were found to be almost three times the risk of cervical dysplasia than females with CC genotype [OR, 2.9; (CI, 1.5-5.7)], but were less likely to develop squamous cell carcinoma [OR, 1.5 (CI, 0.7-3.2)]. Similar findings were observed for mutation at 1298 position, females with AC/CC genotypes were almost four times the risk of cervical dysplasia [OR, 4.3 (CI, 2.1-9.0)], as compared to AA genotype. Our study lends further support to the hypothesis that the MTHFR polymorphism (677C>T or 1298A>C) is involved in susceptibility to cervical dysplasia. PMID:19356065

Nandan, Naveen Kumar; Wajid, Saima; Biswas, Shilpie; Juneja, Sominder Singh; Rizvi, Moshahid; Prakash, Raminder; Naqvi, Samar Husain

2008-01-01

226

Polymorphisms of methylenetetrahydrofolate reductase gene as the genetic predispositions of coronary artery diseases in eastern India  

PubMed Central

Background: Gene–environment interaction is an important aspect in the development of coronary artery disease (CAD). The mutation (677C-T) of methylenetetrahydrofolate reductase (MTHFR) gene results in a decrease of the enzyme activity that leads to mild hyperhomocysteinemia. Elevated plasma level of homocysteine has been recognized as an independent risk factor for cardiovascular disease. A case–control study was designed to assess whether the prevalence of some MTHFR gene polymorphisms have any role in the development of CAD. Materials and Methods: The study included unrelated 217 cases with CAD and 255 healthy controls. DNA was extracted from peripheral blood. MTHFR genotypes were identified by seeing the presence or absence of 677C?T mutation obtained by PCR followed by Hinf1 restriction digestion. Multiple logistic regression analysis was carried out to find association between studied genotypes and lifestyle as well as biochemical risk factors. Results: The T allele was found to be associated with the disease. Significant associations were found with smoking, hypertension, diabetes, and family history of CAD. Conclusion: The results indicate that MTHFR 677C-T polymorphism has significant association with CADs in the population of eastern India.

Dhar, Soujatya; Chatterjee, Sumana; Ray, Saumitra; Dutta, Anjanlal; Sengupta, Bani; Chakrabarti, Shila

2010-01-01

227

Maternal MTHFR 677C>T is a risk factor for congenital heart defects: effect modification by periconceptional folate supplementation  

Microsoft Academic Search

AIMS: Periconceptional folate supplementation prevents neural tube defects and possibly congenital heart defects (CHD) as well. The search for candidate genes involved in the folate metabolism includes the methylenetetrahydrofolate reductase (MTHFR) 677C > T polymorphism. We studied the association between MTHFR 677C > T variants and CHD risk. The interaction with periconceptional folate supplementation was also investigated. METHODS AND RESULTS:

I. M. van Beijnum; Livia Kapusta; Martin den Heijer; Sita H. H. M. Vermeulen; Margreet Kouwenberg; Otto Daniels; Henk J. Blom

2006-01-01

228

Decreased methylene tetrahydrofolate reductase activity due to the 677C?T mutation in families with spina bifida offspring  

Microsoft Academic Search

Periconceptional folate intake reduces both the occurrence and recurrence risk of neural tube defects. Plasma homocysteine\\u000a levels can be elevated in mothers of a child with a neural tube defect, suggesting a dysfunctional folate metabolism. Very\\u000a recently we showed that a common 677C?T mutation in the 5,10-methylene tetrahydrofolate reductase gene, causing thermolability\\u000a of the enzyme, is a risk factor for

N. M. J. van der Put; L. P. van den Heuvel; R. P. M. Steegers-Theunissen; F. J. M. Trijbels; T. K. A. B. Eskes; E. C. M. Mariman; M. den Heyer; H. J. Blom

1996-01-01

229

COMT and MTHFR polymorphisms interaction on cognition in schizophrenia: an exploratory study.  

PubMed

The investigation of the catechol-O-methyltransferase (COMT-[rs4680]) and methylenetetrahydrofolate reductase (MTHFR-[rs1801133]) polymorphisms' interaction might shed light into the pathogenetic mechanisms of the cognitive dysfunction in schizophrenia. In an exploratory study, we hypothesized that the MTHFR 677T allele which has been related to a hypoactive MTHFR enzyme would augment the unfavorable effects of COMT Val158 homozygosity which has been associated with COMT enzyme hyperfunction. 90 schizophrenia patients and 55 healthy volunteers were assessed on psychomotor speed, pattern and spatial recognition memory (SRM), spatial working memory (SWM), attentional flexibility and planning (Stockings of Cambridge-SOC). IQ scores in a random subgroup of patients were also measured. A significant COMT×MTHFR interaction on SWM (p=0.048) and planning (p=0.026) was revealed in both groups. Among COMT-Val/Val participants, MTHFR-C/C made more SWM errors (p=0.033) and solved fewer SOC problems (p=0.025) than MTHFR-T carriers. In patients, there was a significant COMT×MTHFR interaction on full scale IQ (p=0.035): among COMT-Met carriers, MTHFR-T carriers performed significantly worse than MTHFR-C/C (p=0.021), which was driven by a COMT×MTHFR interaction involving performance IQ (p=0.047). In conclusion, COMT and MTHFR polymorphisms interacted on cognition, suggesting that the MTHFR enzyme activity might moderate the effects of the COMT enzyme. In contrast to our initial hypothesis, the MTHFR T-allele attenuated the cognitive effects of COMT Val homozygosity. In this preliminary study, we propose that dopaminergic and intracellular methylation mechanisms could interact on cognitive deficits in schizophrenia. PMID:23353103

Kontis, Dimitrios; Theochari, Eirini; Fryssira, Helen; Kleisas, Spyridon; Sofocleous, Christalena; Andreopoulou, Angeliki; Kalogerakou, Stamatina; Gazi, Anthia; Boniatsi, Lucia; Chaidemenos, Alexandros; Tsaltas, Eleftheria

2013-01-23

230

Genotyping of two single nucleotide polymorphisms in 5,10-methylenetetrahydrofolate reductase by multiplex polymerase chain reaction and capillary electrophoresis.  

PubMed

Two single nucleotide polymorphisms (SNPs) of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, A1298C and C677T, were widely considered to be related with various neoplasia disorders. We established a simple and effective capillary electrophoresis (CE) method for detection of two SNPs in MTHFR gene simultaneously. DNA samples were amplified by multiplex PCR with universal fluorescence-labeled primer and analyzed by single-strand conformation polymorphism (SSCP)-CE method. The CE method was performed using 1.5% hydroxyethyl cellulose in 1× TBE buffer containing 1M urea. The PCR products after SSCP procedure were electrokinetically injected at -10 kV, 30s. Separation voltage was -6 kV and the temperature was set at 20°C. The optimal SSCP-CE method was applied to detect two polymorphisms in MTHFR gene of acute lymphoblastic leukemia (ALL) and attention-deficit/hyperactivity disorder (ADHD) patients. Genotyping results were evaluated in terms of relationships between outcomes for ADHD patients after ALL chemotherapy and ALL disease. The SSCP-CE method and multiplex PCR with universal fluorescence primer were used as the fast technique for screening two SNPs in MTHFR gene, A1298C and C677T. The genotyping data were coincident with DNA sequencing. This SSCP-CE method was found feasible for detecting mutation of MTHFR gene in populations. PMID:20870238

Cheng, Hui-Ling; Chiou, Shyh-Shin; Liao, Yu-Mei; Chen, Yen-Ling; Wu, Shou-Mei

2010-09-08

231

Hydride transfer catalysed by Escherichia coli and Bacillus subtilis dihydrofolate reductase: coupled motions and distal mutations  

PubMed Central

This paper reviews the results from hybrid quantum/classical molecular dynamics simulations of the hydride transfer reaction catalysed by wild-type (WT) and mutant Escherichia coli and WT Bacillus subtilis dihydrofolate reductase (DHFR). Nuclear quantum effects such as zero point energy and hydrogen tunnelling are significant in these reactions and substantially decrease the free energy barrier. The donor–acceptor distance decreases to ca 2.7?? at transition-state configurations to enable the hydride transfer. A network of coupled motions representing conformational changes along the collective reaction coordinate facilitates the hydride transfer reaction by decreasing the donor–acceptor distance and providing a favourable geometric and electrostatic environment. Recent single-molecule experiments confirm that at least some of these thermally averaged equilibrium conformational changes occur on the millisecond time-scale of the hydride transfer. Distal mutations can lead to non-local structural changes and significantly impact the probability of sampling configurations conducive to the hydride transfer, thereby altering the free-energy barrier and the rate of hydride transfer. E. coli and B. subtilis DHFR enzymes, which have similar tertiary structures and hydride transfer rates with 44% sequence identity, exhibit both similarities and differences in the equilibrium motions and conformational changes correlated to hydride transfer, suggesting a balance of conservation and flexibility across species.

Hammes-Schiffer, Sharon; Watney, James B

2006-01-01

232

Ataxia-telangiectasia mutated kinase regulates ribonucleotide reductase and mitochondrial homeostasis  

PubMed Central

Ataxia-telangiectasia mutated (ATM) kinase orchestrates nuclear DNA damage responses but is proposed to be involved in other important and clinically relevant functions. Here, we provide evidence for what we believe are 2 novel and intertwined roles for ATM: the regulation of ribonucleotide reductase (RR), the rate-limiting enzyme in the de novo synthesis of deoxyribonucleoside triphosphates, and control of mitochondrial homeostasis. Ataxia-telangiectasia (A-T) patient fibroblasts, wild-type fibroblasts treated with the ATM inhibitor KU-55933, and cells in which RR is inhibited pharmacologically or by RNA interference (RNAi) each lead to mitochondrial DNA (mtDNA) depletion under normal growth conditions. Disruption of ATM signaling in primary A-T fibroblasts also leads to global dysregulation of the R1, R2, and p53R2 subunits of RR, abrogation of RR-dependent upregulation of mtDNA in response to ionizing radiation, high mitochondrial transcription factor A (mtTFA)/mtDNA ratios, and increased resistance to inhibitors of mitochondrial respiration and translation. Finally, there are reduced expression of the R1 subunit of RR and tissue-specific alterations of mtDNA copy number in ATM null mouse tissues, the latter being recapitulated in tissues from human A-T patients. Based on these results, we propose that disruption of RR and mitochondrial homeostasis contributes to the complex pathology of A-T and that RR genes are candidate disease loci in mtDNA-depletion syndromes.

Eaton, Jana S.; Lin, Z. Ping; Sartorelli, Alan C.; Bonawitz, Nicholas D.; Shadel, Gerald S.

2007-01-01

233

MTHFR polymorphic variant C677T is associated to vascular complications in sickle-cell disease.  

PubMed

Vaso-occlusion is a determinant for most signs and symptoms of sickle-cell anemia (SCA). The mechanisms involved in the pathogenesis of vascular complications in SCA remain unclear. It is known that genetic polymorphisms associated with thrombophilia may be potential modifiers of clinical features of SCA. The genetic polymorphisms C677T and A1298C relating to the enzyme methylenetetrahydrofolate reductase (MTHFR), a clotting Factor V Leiden mutation (1691G?A substitution of Factor V Leiden), and the mutant prothrombin 20210A allele were analyzed in this study. The aim was to find possible correlations with vascular complications and thrombophilia markers in a group of SCA patients in Pernambuco, Brazil. The study included 277 SCA patients, divided into two groups: one consisting of 177 nonconsanguineous SCA patients who presented vascular manifestations of stroke, avascular necrosis, leg ulcers, priapism, and acute chest syndrome (group 1); and the other consisting of 100 SCA patients without any reported vascular complication (group 2). Molecular tests were done using either polymerase chain reaction (PCR) restriction fragment length polymorphism or allele-specific PCR techniques. Comparisons between the groups were made using the ?(2) test. The 677 CT and TT genotypes showed a significant risk of vascular complications (p=0.015). No significant associations between the groups were found when samples were analyzed for the MTHFR A1298C allele (p=0.913), Factor V G1691 (p=0.555), or prothrombin G20210A mutation (p=1.000). The polymorphism MTHFR C677T seemed to be possibly predictive for the development of some vascular complications in SCA patients among this population. PMID:22924497

Hatzlhofer, Betânia L D; Bezerra, Marcos André C; Santos, Magnun N N; Albuquerque, Dulcinéia M; Freitas, Elizabete M; Costa, Fernando F; Araújo, Aderson S; Muniz, Maria Tereza C

2012-08-27

234

Combination of polymorphisms between MTHFR and TS gene modulates survival after 5-fluorouracil-based therapy in colorectal cancer patients  

Microsoft Academic Search

The major targets of 5-fluorouracil (5-FU) are thymidylate synthase (TS) and methylenetetrahydrofolate reductase (MTHFR).\\u000a Therefore, we hypothesized that the variable number of tandem repeat (VNTR) of the thymidylate synthase enhancer region (TSER) together with methylenetetrahydrofolate reductase (MTHFR 677C>T) polymorphism could alter drug activity and predict drug toxicity or efficacy. This study was designed to investigate\\u000a the influence of TSER and

Jong Woo Kim; Jae Ho Lee; Seung Ho Hong; Dong Jin Yim; Hee Jung An; So Young Chong; Doyeun Oh; Nam Keun Kim

2010-01-01

235

Prevalence of methylenetetrahydrofolate reductase C677T and A1298C polymorphisms in Taiwanese patients with Type 2 diabetic mellitus  

Microsoft Academic Search

ObjectivesDeficiency and\\/or decreased activity of methyltetrahydrofolate reductase (MTHFR) resulted from MTHFR variants are associated with hyperhomocysteinemia, an independent risk factor for vasculopathies in diabetic patients. The aim of this study was to examine MTHFR genotypes between healthy and type 2 diabetes mellitus (T2DM) subjects.

Yih-Hsin Chang; Wen-Mei Fu; Yu-Hui Wu; Chih-Jung Yeh; Chien-Ning Huang; Ming-Yuh Shiau

236

Prenatal diagnosis for severe methylenetetrahydrofolate reductase deficiency by linkage analysis and enzymatic assay.  

PubMed

Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is characterized by varying degrees of developmental delay, motor and gait abnormalities, seizures, and thrombosis. Biochemical abnormalities include homocystinuria and hyperhomocysteinemia. Clinical severity correlates with MTHFR activity in cultured fibroblasts; activity can also be assayed in cultured amniocytes and chorionic villus cells (CVC). Forty-four private mutations have been identified, limiting the use of direct mutation detection for prenatal diagnosis. However, intragenic polymorphisms have been identified, making prenatal diagnosis by linkage analysis a possible option, even without knowledge of deleterious mutations. Prenatal diagnosis for severe MTHFR deficiency has been available by biochemical methodologies, but molecular genetic approaches have not yet been reported. We performed prenatal diagnosis for severe MTHFR deficiency in 11 at-risk pregnancies in seven families. A combined approach of linkage analysis and enzymatic assays was used in six pregnancies; linkage analysis alone was performed in one pregnancy. Linkage analysis for the 677C > T or 1298A > C polymorphisms predicted that all seven fetuses were unaffected. For six of these seven fetuses, enzymatic activities were also measured and demonstrated concordant results. Of the 10 pregnancies in which enzymatic assays were performed, activities in cultured amniocytes predicted six unaffected fetuses (1.4-7.1 nmol CHO/mg prot/h (U)) and one affected fetus (0.24 U [control 3.1-9.6 U]). Three pregnancies assessed via CVCs demonstrated two unaffected fetuses (3.6 and 7.7 U) and 1 affected fetus (0 U [control 4.5-7.8 U]). These values were compared to those of the probands (range = 0.02-0.7 U (control 2.4-11.7 U)) in cultured fibroblasts. Our findings suggest that linkage analysis for severe MTHFR deficiency can be a practical approach for prenatal diagnosis. PMID:15896655

Morel, Chantal F; Scott, Patrick; Christensen, Ernst; Rosenblatt, David S; Rozen, Rima

2005-04-01

237

Interactions between the SNPs in the homocysteine pathway (MTHFR 677C>T, MTHFR 1298 A>C and CBSins) and the efficacy of HMG-CoA reductase inhibitors in preventing cardiovascular disease in high-risk hypertensives: The GenHAT Study  

PubMed Central

Background High homocysteine blood concentrations predispose to coronary artery disease and statins influence homocysteine levels. Aim To study whether genes that regulate homocysteine metabolism interact with statins to modify the risk of CHD and other cardiovascular outcomes. Methods GenHAT is an ancillary study of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). The genotyped population in the lipid lowering trial (LLT) of ALLHAT included 9,624 participants randomly assigned to pravastatin or to usual care. The efficacy of pravastatin in reducing risk of all-cause mortality and CHD was compared among genotype strata (MTHFR 677 CC, CT and TT, MTHFR 1298 AA, AC, and CC, CBSins DD and I+) by examining an interaction term in a proportional hazards model. Results There was no evidence of a pharmacogenetic effect on statins with the MTHFR 1298 A>C genotype for CHD risk. However, in persons with the CC variant for the MTHFR 677 C>T genotype a significantly protective effect against CHD (0.71 (95% CI 0.58–0.87)) was shown. While in the CT (1.25 (95% CI 0.97–1.61) and TT groups (0.80 (95% CI 0.50–1.28) there were no such effects (interaction hazard ratio p=0.004) The CBSins, I+ variant was associated with a significantly reduced risk for CHD among those on statin treatment (0.58 (95% CI 0.44–0.78)) while the DD genotype showed no effect from statin therapy (1.01 (95% CI 0.84–1.20; p=0.002 for interaction). For the endpoint all-cause mortality, no significant differences in efficacy were noted. Conclusions Polymorphisms in genes in the homocysteine pathway (MTHFR 677 C>T and CBSins) appear to modify the efficacy of pravastatin in reducing risk of cardiovascular events.

Maitland-van der Zee, Anke-Hilse; Lynch, Amy; Boerwinkle, Eric; Arnett, Donna K.; Davis, Barry R.; Leiendecker-Foster, Catherine; Ford, Charles E.; Eckfeldt, John H.

2008-01-01

238

The association between methylene-tetrahydrofolate reductase gene polymorphism and lung cancer risk.  

PubMed

This study aimed to determine the relation between methylene-tetrahydrofolate reductase (MTHFR) gene polymorphism and lung cancer risk and the frequency of this polymorphism. The study involved 64 lung cancer patients (the study group) with definitive diagnosis and 61 noncancerous subjects (the control group). MTHFR C677T and A1298C mutation analysis was made using DNA isolated from peripheric blood and multiplex PCR and reverse hybridization strip test. Eighty-four percent of the patients were male. The age, gender, and history of alcohol use of the patients and control group were statistically similar. While MTHFR 677T and 677C allele frequency was 0.33 and 0.67 in the patients respectively, it was 0.29 and 0.71 in the control group. The frequencies of MTHFR 1298C and 1298A were 0.33 and 0.67 in the patients, and it was 0.31 and 0.69 in the control group respectively. When MTHFR 677TT and 677CT genotypes were compared with 677CC genotype, lung cancer risk was 2.4 times higher in the 677TT genotype. When MTHFR 1298AC and 1298CC genotypes were compared with 1298AA genotype, lung cancer risk was 1.5 times higher in 1298CC genotype. According to the results, allele frequency of homozygote T and C was high in lung cancer patients. It was 3.05 and 1.29 times higher in smokers than in non-smokers, and 3.05 and 1.64 times higher in males than in females; 3.0 and 2.44 times higher in those with non-small cell lung cancer than in those with small-cell lung cancer. PMID:20532637

Arslan, Sulhattin; Karadayi, Sule; Yildirim, Malik Ejder; Ozdemir, Ozturk; Akkurt, Ibrahim

2010-06-08

239

Sex-dependent behavioral effects of Mthfr deficiency and neonatal GABA potentiation in mice.  

PubMed

The methylenetetrahydrofolate reductase (Mthfr) gene and/or abnormal homocysteine-folate metabolism are associated with increased risk for birth defects and neuropsychiatric diseases. In addition, disturbances of the GABAergic system in the brain as well as Mthfr polymorphism are associated with neurodevelopmental disorders such as schizophrenia and autism. In the present study we performed behavioral phenotyping of male and female Mthfr mice (wild type and their heterozygous littermates). The present study addresses two main questions: (1) genetic susceptibility, as examined by effects of Mthfr deficiency on behavior (Experiment 1) and (2) possible gene-drug interactions as expressed by behavioral phenotyping of Mthfr-deficient mice neonatally exposed to the GABA potentiating drug GVG (Experiment 2). Newborn development was slightly influenced by Mthfr genotype per se (Experiment 1); however the gene-drug interaction similarly affected reflex development in both male and female offspring (Experiment 2). Hyperactivity was demonstrated in Mthfr heterozygous male mice (Experiment 1) and due to GVG treatment in both Wt and Mthfr+/- male and female mice (Experiment 2). The gene-environment interaction did not affect anxiety-related behavior of male mice (Experiment 2). In female mice, gene-treatment interactions abolished the reduced anxiety observed due to GVG treatment and Mthfr genotype (Experiment 2). Finally, recognition memory of adult mice was impaired due to genotype, treatment and the gene-treatment combination in a sex-independent manner (Experiment 2). Overall, Mthfr deficiency and/or GABA potentiation differentially affect a spectrum of behaviors in male and female mice. This study is the first to describe behavioral phenotypes due to Mthfr genotype, GVG treatment and the interaction between these two factors. The behavioral outcomes suggest that Mthfr deficiency modulates the effects of GABA potentiating drugs. These findings suggest that future treatment strategies should consider a combination of genotyping with drug regimens. PMID:20813139

Levav-Rabkin, Tamar; Blumkin, Elinor; Galron, Dalia; Golan, Hava M

2010-09-08

240

Cerebral sinus venous thrombosis in a subject with thyrotoxicosis and MTHFR gene polymorphism  

Microsoft Academic Search

We report a case of cerebral venous thrombosis (CVT) due to tyrotoxicosis in a patient with methylenetetrahydro-folate-reductase\\u000a (MTHFR) gene polymorphism C677T, (genotype 677TT), in which discontinuation of intravenous heparin was followed by clinical\\u000a and radiological worsening despite warfarin treatment. We discuss the relationship between CVT, MTHFR hyperthiroidism and\\u000a anticoagulant therapy.

Laura Strada; Carlo Gandolfo; Massimo Del Sette

2008-01-01

241

MTHFR Gene Polymorphism and Its Relationship with Plasma Homocysteine and Folate in a North Indian Population  

Microsoft Academic Search

There is a paucity of data on the prevalence of elevated homocysteine and its relation with plasma folate and the methylenetetrahydrofolate\\u000a reductase (MTHFR) gene in the population of North India. This study evaluates MTHFR gene polymorphism and its relationship with plasma homocysteine and folate levels in a healthy North Indian population. The\\u000a age of the 200 subjects included in this

Usha Kant Misra; Jayantee Kalita; Amit Kumar Srivastava; Suraksha Agarwal

2010-01-01

242

Effect of MTHFR 677C>T on plasma total homocysteine levels in renal graft recipients  

Microsoft Academic Search

Effect of MTHFR 677C>T on plasma total homocysteine levels in renal graft recipients.BackgroundHyperhomocysteinemia is an established, independent risk factor for vascular disease morbidity and mortality. The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism C677T has been shown to result in increased total homocysteine concentrations on the basis of low folate levels caused by a decreased enzyme activity. The effect of this polymorphism

MANUELA FÖDINGER; GABRIELE WÖLFL; GOTTFRIED FISCHER; SUSANNE RASOUL-ROCKENSCHAUB; RAINER SCHMID; WALTER H. HORL; GERE SUNDER-PLASSMANN

1999-01-01

243

Riboflavin Lowers Homocysteine in Individuals Homozygous for the MTHFR 677C3T Polymorphism  

Microsoft Academic Search

Background—Meta-analyses predict that a 25% lowering of plasma homocysteine would reduce the risk of coronary heart disease by 11% to 16% and stroke by 19% to 24%. Individuals homozygous for the methylenetetrahydrofolate reductase (MTHFR) 677C3T polymorphism have reduced MTHFR enzyme activity resulting from the inappropriate loss of the riboflavin cofactor, but it is unknown whether their typically high homocysteine levels

Helene McNulty; Le Roy; C. Dowey; J. J. Strain; Adrian Dunne; Mary Ward; Anne M. Molloy; Liadhan B. McAnena; Joan P. Hughes; Mary Hannon-Fletcher; John M. Scott

244

MTHFR polymorphisms, dietary folate intake and breast cancer risk in Chinese women  

Microsoft Academic Search

To evaluate the relationship between dietary folate intake and genetic polymorphisms of 5,10-methylenetetrahydrofolate reductase (MTHFR) with reference to breast cancer risk, we conducted a case–control study with 669 cases and 682 population-based controls in the Jiangsu Province of China. MTHFR C677T and A1298C genotypes were identified using PCR–RFLP (restrictrion fragment length polymorphism) methods. Dietary folate intake was assessed using an

Chang-Ming Gao; Jin-Hai Tang; Hai-Xia Cao; Jian-Hua Ding; Jian-Zhong Wu; Jie Wang; Yan-Ting Liu; Su-Ping Li; Ping Su; Keitaro Matsuo; Toshiro Takezaki; Kazuo Tajima

2009-01-01

245

MTHFR Polymorphisms Involved in Vitamin B 12 Deficiency Associated with Atrophic Gastritis  

Microsoft Academic Search

Genetic polymorphisms affecting methylentetrahydrofolate reductase (MTHFR) activity may influence hematological and neurological\\u000a dysfunction in cobalamin-deficient patients. We studied the prevalence of C677T and A1298C polymorphisms by analyzing genomic\\u000a DNA in 30 cobalamin-deficient patients. No significant difference was found in 677 and 1298 genotype distribution with respect\\u000a to hematological parameters, B12 and folate levels, and neurological symptoms. The two MTHFR polymorphisms

Mariangela Palladino; Patrizia Chiusolo; Giovanni Reddiconto; Sara Marietti; Daniela De Ritis; Giuseppe Leone; Simona Sica

2009-01-01

246

Prevalence of methylenetetrahydrofolate reductase C677T polymorphism in eastern Uttar Pradesh  

PubMed Central

AIM: This study was aimed to evaluate the 5, 10-methylenetetrahydrofolate reductase (MTHFR) C677T mutation in eastern Uttar Pradesh population. MATERIALS AND METHODS: Polymerase chain reaction (PCR) using specific primers followed by amplicon digestion by Hinf I restriction enzyme was used for MTHFR C677T polymorphism analysis. Total 250 subjects were analyzed. RESULTS: The CC genotype was found in 192 subjects, followed by CT in 56 subjects and TT in 2 subject. Genotype frequencies of CC, CT and TT were 0.768, 0.224 and 0.008, respectively. The frequency of C allele was found to be 0.88 and that of T allele was 0.12. CONCLUSION: It is evident from the results of the present study that the percentage of homozygous genotype (CC) is highest in the target population.

Rai, Vandana; Yadav, Upendra; Kumar, Pradeep

2012-01-01

247

Methylenetetrahydrofolate reductase variant and schizophrenia/depression.  

PubMed

Patients with methylenetetrahydrofolate reductase (MTHFR) deficiency often show psychiatric manifestations. Since a common variant of the MTHFR gene, T677(Ala), responsible for the thermolabile MTHFR with less than 50% specific MTHFR activity, has been reported, we examined whether the T677 allele is associated with psychiatric disorders in an unrelated Japanese population consisting of 297 schizophrenics, 32 patients with major depression, 40 patients with bipolar disorder, and 419 controls. The genotype homozygous for the T677 allele was significantly frequently observed in schizophrenics with an odds ratio of 1.9 (P = 0.0006), and in patients with major depression with an odds ratio of 2.8 (P = 0.005). Our data suggest associations of the MTHFR gene variant with schizophrenia and depression in the Japanese. PMID:9342205

Arinami, T; Yamada, N; Yamakawa-Kobayashi, K; Hamaguchi, H; Toru, M

1997-09-19

248

Genotype and haplotype distributions of MTHFR 677C>T and 1298A>C single nucleotide polymorphisms: a meta-analysis  

Microsoft Academic Search

.  ?Common single nucleotide polymorphisms (SNPs; 677C>T and 1298A>C) in the methylenetetrahydrofolate reductase gene (MTHFR) decrease the activity of the enzyme, leading to hyperhomocysteinemia, particularly in folate-deficient states. We calculate\\u000a herein the haplotype frequencies of the MTHFR 677 and 1298 polymorphisms in pooled general populations derived from published data. We selected 16 articles that provided\\u000a reliable data on combined MTHFR genotypes

Shuji Ogino; Robert B. Wilson

2003-01-01

249

Evidence that a point mutation in dihydrofolate reductase-thymidylate synthase confers resistance to pyrimethamine in falciparum malaria.  

PubMed Central

Analysis of a genetic cross of Plasmodium falciparum and of independent parasite isolates from Southeast Asia, Africa, and South America indicates that resistance to pyrimethamine, an antifolate used in the treatment of malaria, results from point mutations in the gene encoding dihydrofolate reductase-thymidylate synthase (EC 1.5.1.3 and EC 2.1.1.45, respectively). Parasites having a mutation from Thr-108/Ser-108 to Asn-108 in DHFR-TS are resistant to the drug. The Asn-108 mutation occurs in a region analogous to the C alpha-helix bordering the active site cavity of bacterial, avian, and mammalian enzymes. Additional point mutations (Asn-51 to Ile-51 and Cys-59 to Arg-59) are associated with increased pyrimethamine resistance and also occur at sites expected to border the active site cavity. Analogies with known inhibitor/enzyme structures from other organisms suggest that the point mutations occur where pyrimethamine contacts the enzyme and may act by inhibiting binding of the drug. Images

Peterson, D S; Walliker, D; Wellems, T E

1988-01-01

250

Maternal MTHFR polymorphisms and risk of spontaneous abortion  

Microsoft Academic Search

Objective. To asses the association between intake of folate and B vitamins and the incidence of spontaneous abortion (SA) according to the maternal methylenetetrahydrofolate reductase (MTHFR) polymorphisms (677 C>T and 1298 A>C). Material and Methods. We conducted a nested case-control study within a perinatal cohort of women re - cruited in the state of Morelos, Mexico. Twenty-three women with SA

María del Rosario Rodríguez-Guillén; Luisa Torres-Sánchez; Jia Chen; Marcia Galván-Portillo; Julia Blanco-Muńoz; Miriam Aracely Anaya; Irma Silva-Zolezzi; María A Hernández-Valero; Lizbeth López-Carrillo

2009-01-01

251

Methylenetetrahydrofolate reductase C677T polymorphism and predisposition towards esophageal squamous cell carcinoma in a German Caucasian and a northern Chinese population  

Microsoft Academic Search

Purpose Folate deficiency is considered to increase the risk of developing esophageal cancer. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme involved in folate metabolism. A single C ? T substitution at nucleotide 677 of the MTHFR cDNA influences enzyme activity. The purpose of this study is to compare the association of the MTHFR C677T polymorphism with susceptibility to esophageal squamous

Jianhui Zhang; Rainer B. Zotz; Yan Li; Rui Wang; Sybille Kiel; Wolfgang A. Schulz; Denggui Wen; Zhifeng Chen; Liwei Zhang; Shijie Wang; Helmut E. Gabbert; Mario Sarbia

2004-01-01

252

Prothrombotic polymorphisms, mutations, and their association with pediatric non-cardioembolic stroke in Asian-Indian patients.  

PubMed

Genes involved in the hemostatic mechanism are logical candidate genes for association studies in prothrombotic conditions such as stroke. Since the underlying etiology in pediatric strokes is different than adults, looking for genetic causes would be the logical thing to do in the pediatric stroke population. Fifty-eight Asian-Indian stroke patients below 15 years of age and equal number of age- and sex-matched healthy controls were the subjects for the study. The subjects were screened for 13 polymorphisms and three mutations spread across seven different candidate genes involved in the hemostatic system. Of the 13 polymorphisms and three mutations studied, four polymorphisms, HPA-I, TAFI 147Ala>Thr, methylene tetrahydrofolate reductase (MTHFR) 677 C>T, and MTHFR 1298 A>C, showed significant association with the disease phenotype. MTHFR 677 C>T showed the strongest association and therefore may have a strong predisposing role for pediatric strokes. Gene-gene interaction studies showed a strong interaction between HPA-I and MTHFR 677 C>T polymorphism. The wild type of both these polymorphisms synergistically showed a strong protective effect [p < 0.0001, O.R: 10.06(4.26-23.71)]. Polymorphisms in HPA-I and MTHFR may have important predisposing roles in the development of pediatric stroke. PMID:18836720

Biswas, Arijit; Tiwari, Arun Kumar; Ranjan, Ravi; Meena, Arvind; Akhter, Mohammad Suhail; Yadav, Birendra Kumar; Behari, Madhuri; Saxena, Renu

2008-10-04

253

MTHFR 677 CT\\/MTHFR 1298 CC genotypes are associated with increased risk of hypertension in Indians  

Microsoft Academic Search

The goals of our present study were to measure plasma homocysteine levels and determine their association with methylenetetrahydrofolate\\u000a reductase (MTHFR) gene polymorphisms (C677T and A1298C) in essential hypertensive subjects. Plasma total homocysteine and\\u000a folic acid levels were measured in essential hypertensive patients (n = 153) before and after oral supplementation with either 5 mg folic acid tablet\\/day or 5 mg placebo\\/day for 4 weeks and

Suchita Markan; Meenakshi Sachdeva; Badan Singh Sehrawat; Savita Kumari; Sanjay Jain; Madhu Khullar

2007-01-01

254

Evaluation of the MTHFR C677T allele and the MTHFR gene locus in a German spina bifida population  

Microsoft Academic Search

A number of recent studies have demonstrated that the occurrence and recurrence risk of neural tube defects (NTD) is reduced\\u000a by folic acid supplementation before and during pregnancy. Epidemiological studies have shown low plasma folate and raised\\u000a plasma homocysteine in women with spina bifida aperta (SB) children suggesting an abnormal folate metabolism. The 5,10-methylenetetrahydrofolate\\u000a reductase (MTHFR) variant C677T, resulting in

M. C. Koch; K. Stegmann; A. Ziegler; B. Schröter; A. Ermert

1998-01-01

255

Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition.  

PubMed

Hyperhomocysteinemia, a risk factor for cardiovascular disease, is caused by nutritional and/or genetic disruptions in homocysteine metabolism. The most common genetic cause of hyperhomocysteinemia is the 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene. This variant, with mild enzymatic deficiency, is associated with an increased risk for neural tube defects and pregnancy complications and with a decreased risk for colon cancer and leukemia. Although many studies have reported that this variant is also a risk factor for vascular disease, this area of investigation is still controversial. Severe MTHFR deficiency results in homocystinuria, an inborn error of metabolism with neurological and vascular complications. To investigate the in vivo pathogenetic mechanisms of MTHFR deficiency, we generated mice with a knockout of MTHFR: Plasma total homocysteine levels in heterozygous and homozygous knockout mice are 1.6- and 10-fold higher than those in wild-type littermates, respectively. Both heterozygous and homozygous knockouts have either significantly decreased S-adenosylmethionine levels or significantly increased S-adenosylhomocysteine levels, or both, with global DNA hypomethylation. The heterozygous knockout mice appear normal, whereas the homozygotes are smaller and show developmental retardation with cerebellar pathology. Abnormal lipid deposition in the proximal portion of the aorta was observed in older heterozygotes and homozygotes, alluding to an atherogenic effect of hyperhomocysteinemia in these mice. PMID:11181567

Chen, Z; Karaplis, A C; Ackerman, S L; Pogribny, I P; Melnyk, S; Lussier-Cacan, S; Chen, M F; Pai, A; John, S W; Smith, R S; Bottiglieri, T; Bagley, P; Selhub, J; Rudnicki, M A; James, S J; Rozen, R

2001-03-01

256

Acute leukoencephalopathy possibly induced by phenytoin intoxication in an adult patient with methylenetetrahydrofolate reductase deficiency.  

PubMed

A 19-year-old university student with no personal or family history of neurologic disorders developed convulsions and was administered phenytoin. Two months later, he developed lower limb-dominant acute demyelinating polyneuropathy, from which he recovered within 2 months. At age 20, he rapidly developed visual disturbances and paraplegia from phenytoin intoxication. Cranial magnetic resonance imaging (MRI) revealed leukoencephalopathy with no evidence of thrombosis or vasoconstriction. Hyperhomocysteinemia, hypomethioninemia, low serum folate concentration, and an absence of megaloblastic anemia were consistent with the diagnosis of methylenetetrahydrofolate reductase (MTHFR) deficiency. A genomic DNA sequence analysis demonstrated compound heterozygosity for two missense mutations in the MTHFR gene, namely, [458G>T?+?459C>T] (Gly149Val) and 358G>A (Ala116Thr), both of which are known pathogenic mutations. An absence of leukoencephalopathic changes on MRI scans performed 9 months previously strongly suggested that phenytoin intoxication caused acute leukoencephalopathy. Therefore, phenytoin may be an aggravating factor of remethylation defects in patients with MTHFR deficiency. PMID:21480888

Arai, Motomi; Osaka, Hitoshi

2011-04-11

257

Betaine rescue of an animal model with methylenetetrahydrofolate reductase deficiency.  

PubMed

MTHFR (methylenetetrahydrofolate reductase) catalyses the synthesis of 5-methyltetrahydrofolate, the folate derivative utilized in homocysteine remethylation to methionine. A severe deficiency of MTHFR results in hyperhomocysteinaemia and homocystinuria. Betaine supplementation has proven effective in ameliorating the biochemical abnormalities and the clinical course in patients with this deficiency. Mice with a complete knockout of MTHFR serve as a good animal model for homocystinuria; early postnatal death of these mice is common, as with some neonates with low residual MTHFR activity. We attempted to rescue Mthfr-/- mice from postnatal death by betaine supplementation to their mothers throughout pregnancy and lactation. Betaine decreased the mortality of Mthfr-/- mice from 83% to 26% and significantly improved somatic development from postnatal day 1, compared with Mthfr-/- mice from unsupplemented dams. Biochemical evaluations demonstrated higher availability of betaine in suckling pups, decreased accumulation of homocysteine, and decreased flux through the trans-sulphuration pathway in liver and brain of Mthfr-/- pups from betaine-supplemented dams. We observed disturbances in proliferation and differentiation in the cerebellum and hippocampus in the knockout mice; these changes were ameliorated by betaine supplementation. The dramatic effects of betaine on survival and growth, and the partial reversibility of the biochemical and developmental anomalies in the brains of MTHFR-deficient mice, emphasize an important role for choline and betaine depletion in the pathogenesis of homocystinuria due to MTHFR deficiency. PMID:15217352

Schwahn, Bernd C; Laryea, Maurice D; Chen, Zhoutao; Melnyk, Stepan; Pogribny, Igor; Garrow, Timothy; James, S Jill; Rozen, Rima

2004-09-15

258

Betaine rescue of an animal model with methylenetetrahydrofolate reductase deficiency  

PubMed Central

MTHFR (methylenetetrahydrofolate reductase) catalyses the synthesis of 5-methyltetrahydrofolate, the folate derivative utilized in homocysteine remethylation to methionine. A severe deficiency of MTHFR results in hyperhomocysteinaemia and homocystinuria. Betaine supplementation has proven effective in ameliorating the biochemical abnormalities and the clinical course in patients with this deficiency. Mice with a complete knockout of MTHFR serve as a good animal model for homocystinuria; early postnatal death of these mice is common, as with some neonates with low residual MTHFR activity. We attempted to rescue Mthfr?/? mice from postnatal death by betaine supplementation to their mothers throughout pregnancy and lactation. Betaine decreased the mortality of Mthfr?/? mice from 83% to 26% and significantly improved somatic development from postnatal day 1, compared with Mthfr?/? mice from unsupplemented dams. Biochemical evaluations demonstrated higher availability of betaine in suckling pups, decreased accumulation of homocysteine, and decreased flux through the trans-sulphuration pathway in liver and brain of Mthfr?/? pups from betaine-supplemented dams. We observed disturbances in proliferation and differentiation in the cerebellum and hippocampus in the knockout mice; these changes were ameliorated by betaine supplementation. The dramatic effects of betaine on survival and growth, and the partial reversibility of the biochemical and developmental anomalies in the brains of MTHFR-deficient mice, emphasize an important role for choline and betaine depletion in the pathogenesis of homocystinuria due to MTHFR deficiency.

2004-01-01

259

Expression of the Volvox gene encoding nitrate reductase: Mutation-dependent activation of cryptic splice sites and intron-enhanced gene expression from a cDNA  

Microsoft Academic Search

Use of the nitrate reductase encoding gene (nitA) as selection marker has facilitated the successful nuclear transformation of Volvox carteri. The Volvox nitA gene contains 10 introns. A stable nitA mutation in the Volvox recipient strain 153–81 resides in a G-to-A transition of the first nucleotide in the 5' splice site of nitA intron 2. This mutation resulted in at

Heribert Gruber; Stefan H. Kirzinger; Rüdiger Schmitt

1996-01-01

260

Targeted insertion of two Mthfr promoters in mice reveals temporal- and tissue-specific regulation.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate metabolism, synthesizes 5-methyltetrahydrofolate, the main circulatory form of folate which is required for maintaining nontoxic levels of homocysteine and providing one-carbon units for methylation. A common 677C ? T variant in MTHFR confers mild MTHFR deficiency and has been associated with a number of human disorders, including neural tube defects and vascular disease. Two promoters of Mthfr, designated as upstream and downstream promoters, are located upstream of a transcription start site cluster and have previously demonstrated cell-specific activities. In this study we used a unique approach for targeted, single-copy transgene insertion to generate transgenic mice carrying a Mthfr upstream or Mthfr downstream promoter-reporter construct located 5' to the endogenous Hprt (hypoxanthine-guanine phosphoribosyltransferase) locus. The Mthfr downstream promoter demonstrated activity in the neural tube, neural crest cells, dorsal root ganglia, heart, and endothelial cells of blood vessels in 10.5-days post coitum embryos and placentas. Upstream promoter activity was absent at this developmental stage. Postnatally, both promoters demonstrated activity in the brain stem, hippocampus, and thalamus of 1-week-old brain that became stronger in the adult. The Mthfr upstream promoter also showed activity in the cerebellum and cerebral cortex. Both promoters were active in male reproductive tissues, including 1-week-old epididymides, and there was upstream promoter-specific activity in the adult testis. Our investigation of Mthfr regulation in an in vivo mouse model revealed temporal- and tissue-specific regulation that supports important roles for MTHFR in the developing embryo, and in postnatal brain and male reproductive tissues. PMID:21769670

Pickell, Laura; Wu, Qing; Wang, Xiao-Ling; Leclerc, Daniel; Friedman, Hana; Peterson, Alan C; Rozen, Rima

2011-07-19

261

The 5, 10 methylenetetrahydrofolate reductase C677T mutation and risk of fetal loss: a case series and review of the literature  

Microsoft Academic Search

BACKGROUND: The true relationship between methylenetetrahydrofolate reductase C677T homozygosity and risk of recurrent spontaneous abortion is unknown, and it is unclear if women with these mutations should be anticoagulated during pregnancy. OBJECTIVES: We report a series of 8 patients with this issue and review the current literature. METHODS: 8 patients (3 of whom were actively pregnant) were referred with histories

Ivy Altomare; Alan Adler; Louis M Aledort

2007-01-01

262

No association with the 5,10-methylenetetrahydrofolate reductase gene and major depressive disorder: results of the depression case control (DeCC) study and a meta-analysis.  

PubMed

Unipolar major depressive disorder (MDD) is a complex disorder thought to result from multiple genes in combination with environmental and developmental components. The 5,10-methylenetetrahydrofolate reductase gene (MTHFR) has been implicated in MDD in a meta-analysis of association studies and is within a linkage region suggested by a recent study of affected sib pairs. A single base mutation in the MTHFR gene (C677T) results in the production of a mildly dysfunctional thermolabile enzyme. The MTHFR 677TT genotype, and to a lesser extent the 677CT genotype, is associated with a significant elevation in the circulating concentrations of homocysteine and a decrease in serum folate concentrations. This may parallel a similar reduction in 5-methyltetrahydrofolate in the CNS, leading to a potential reduction in monoamine neurotransmitter function and an elevated risk of depressive disorder. To test the hypothesis that the MTHFR C677T polymorphism is involved in the predisposition to MDD, we conducted an association study of 1,222 patients with recurrent MDD and 835 control subjects. This allows 99% power to detect an effect of the size reported in the study of Bjelland et al. 2003, however no significant differences in genotype or allele frequencies between depressive patients and controls were observed. This was the case in the sample as a whole, and when females and males were considered separately. Our findings suggest that the MTHFR C677T polymorphism is not involved in the etiology of clinically significant recurrent MDD. PMID:18165972

Gaysina, D; Cohen, S; Craddock, N; Farmer, A; Hoda, F; Korszun, A; Owen, M J; Craig, I W; McGuffin, P

2008-09-01

263

Ramifications of four concurrent thrombophilic mutations and one hypofibrinolytic mutation.  

PubMed

A kindred was examined in which the 48-year-old white female proband with three deep venous thrombosis-pulmonary emboli events had four thrombophilic and one hypofibrinolytic mutations, and in which her 14-year-old asymptomatic daughter had four thrombophilic mutations. The proband was heterozygous for the G1691A factor V Leiden, G20210A prothrombin, and platelet glycoprotein IIIa PL A1/A2 mutations, had high factor VIII (221%), and was homozygous for the 4G4G plasminogen activator inhibitor-1 gene mutation, with high plasminogen activator inhibitor activity (23.7 U/mL). Her 14-year-old daughter was homozygous for the G1691A factor V Leiden and platelet glycoprotein IIb-IIIa PL A2/A2 mutations, compound heterozygous for the C677T and A1298C methylenetetrahydrofolate reductase (MTHFR) mutations, and heterozygous for the G20210A prothrombin mutation, a combination with an estimated likelihood of 1.6 x 10(-7). In 247 white healthy controls, there was no V Leiden homozygosity and no V Leiden-prothrombin gene compound heterozygosity. Heterozygosity for the V Leiden and prothrombin gene mutations was 3.2% and 4.1%, respectively. Homozygosity for the platelet glycoprotein IIb-IIIa PL A2A2, PAI-1 gene 4G4G, and C677T MTHFR mutations was 3.2%, 22.7%, and 12%, respectively. The proband will receive anticoagulation therapy for life. Beyond aspirin, avoidance of exogenous estrogens, and enoxaparin prophylaxis during pregnancy, it is not known whether the proband's daughter should have lifelong anticoagulation therapy, or only after her first thrombotic event. PMID:15497023

Glueck, Charles J; Goldenberg, Naila; Wang, Ping; Aregawi, Dawit

2004-10-01

264

Hyperhomocysteinemia is associated with hypertriglyceridemia in mice with methylenetetrahydrofolate reductase deficiency.  

PubMed

Hyperhomocysteinemia (HHcy) can result from genetic or nutritional disturbances in folate metabolism. The most common genetic cause of mild HHcy is methylenetetrahydrofolate reductase (MTHFR) deficiency. To explore interactions between HHcy and lipid metabolism in atherogenesis, we measured plasma homocysteine (Hcy), triglycerides and cholesterol in Mthfr(+/+) and Mthfr(+/-) mice on C57BL/6 and BALB/c backgrounds, fed control or folate-deficient diets. We also crossed ApoE(C57)(-/-) mice with Mthfr(C57)(+/-) and Mthfr(BALB/c)(+/-) mice, and examined the same plasma variables as well as lipid accumulation in aortic sinus and whole aorta. Mthfr(+/-) mice had significantly higher plasma Hcy and plasma triglycerides relative to Mthfr(+/+) mice. A significant positive correlation was observed between plasma Hcy and plasma triglycerides in all mice. Mthfr(+/-) mice had lower plasma ApoA-IV protein levels which could reduce clearance of triglyceride-rich lipoproteins from the circulation. In the double mutant experiments, plasma Hcy was higher in Mthfr(+/-) compared with Mthfr(+/+) in ApoE(C57)(-/-)/Mthfr(C57) and ApoE(C57)(-/-)/Mthfr(BALB/c) mice. Triglycerides in female ApoE(C57)(-/-)/Mthfr(BALB/c)(+/-) mice were higher than those in ApoE(C57)(-/-)/Mthfr(BALB/c)(+/-) mice and correlated positively with Hcy. ApoE(C57)(-/-)/Mthfr(C57)(+/-) male mice had more lipid deposition in aortic sinus and whole aorta compared with ApoE(C57)(-/-)/Mthfr(c57)(+/+) mice. Our results suggest that HHcy is associated with hypertriglyceridemia and that MTHFR deficiency may exacerbate lipid accumulation in ApoE deficiency. PMID:19560954

Mikael, Leonie G; Wang, Xiao-Ling; Wu, Qing; Jiang, Hua; Maclean, Kenneth N; Rozen, Rima

2009-06-23

265

[Mutational research on the role of lysine 21 in the Pichia stipitis xylose reductase].  

PubMed

The xylose reductase of Pichia stipitis is one of the most important enzymes. It can be used to build up recombinant Saccharomyces cerevisiae strain for utilizing xylose and producing ethanol. Intercellular redox imbalance caused by NADPH preference over NADH for Pichia stipitis xylose reductase (PsXR) has been considered to be one of the main factors for poor ethanol productivity. Some key amino acids of PsXR, which affect the activity or coenzyme preference, were investigated in our previous study. In this study, Lys21 were rational designed for site-directed mutagenesis to alter coenzyme specificity of PsXR from NADPH and NADH into single NADH. The wild gene and mutagenesis genes were ligated into pET28b, and were transferred into E.coli BL21(DE3). After induced by IPTG, the xylose reductases were purified. Purified mutants K21A (Lys21-->Ala), K21R(Lys21-->Arg) were characterized by steady-state kinetic analysis. The results showed that the coenzyme dependence of K21A was completely reversed to NADH. PMID:18808001

Zeng, Qikai; Du, Hongli; Zhai, Zhichen; Lin, Xiaoqiong; Lin, Ying

2008-06-01

266

MTHFR Polymorphisms as Prognostic Factors in Sporadic Colorectal Cancer  

Microsoft Academic Search

Aim. Theoretically, individuals having at least one mutant allele present a modified activity of the MTHFR enzyme and low methylation, DNA synthesis-repair respectively, which could imply a higher risk of colorectal cancer. The purpose of this study was to investigate the relations of these mutations with the clinico-pathological aspects of colorectal cancer. Material and method. The study included 69 patients

Gelu Osian; Lucia Procopciuc; Liviu Vlad

267

Modulating radiation resistance by inhibiting ribonucleotide reductase in cancers with virally or mutationally silenced p53 protein.  

PubMed

Therapeutic ionizing radiation damages DNA, increasing p53-regulated ribonucleotide reductase (RNR) activity required for de novo synthesis of the deoxyribonucleotide triphosphates used during DNA repair. This study investigated the pharmacological inhibition of RNR in cells of virally or mutationally silenced p53 cancer cell lines using 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine(R), NSC #663249), a chemotherapeutic radiosensitizer that equally inhibits RNR M2 and p53R2 small subunits. The effects of 3-AP on RNR inhibition and resulting radiosensitization were evaluated in cervical (CaSki, HeLa and C33-a) and colon (RKO, RKO-E6) cancer cells. 3-AP treatment significantly enhanced radiation-related cytotoxicity in cervical and colon cancer cells. 3-AP treatment significantly decreased RNR activity, caused prolonged radiation-induced DNA damage, and resulted in an extended G(1)/S-phase cell cycle arrest in all cell lines. Similar effects were observed in both RKO and RKO-E6 cells, suggesting a p53-independent mechanism of radiosensitization. We conclude that inhibition of ribonucleotide reductase by 3-AP enhances radiation-mediated cytotoxicity independent of p53 regulation by impairing repair processes that rely on deoxyribonucleotide production, thereby substantially increasing the radiation sensitivity of human cancers. PMID:19929413

Kunos, Charles A; Chiu, Song-mao; Pink, John; Kinsella, Timothy J

2009-12-01

268

Modulating Radiation Resistance by Inhibiting Ribonucleotide Reductase in Cancers with Virally or Mutationally Silenced p53 Protein  

PubMed Central

Therapeutic ionizing radiation damages DNA, increasing p53-regulated ribonucleotide reductase (RNR) activity required for de novo synthesis of the deoxyribonucleotide triphosphates used during DNA repair. This study investigated the pharmacological inhibition of RNR in cells of virally or mutationally silenced p53 cancer cell lines using 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine® NSC #663249), a chemotherapeutic radiosensitizer that equally inhibits RNR M2 and p53R2 small subunits. The effects of 3-AP on RNR inhibition and resulting radiosensitization were evaluated in cervical (CaSki, HeLa and C33-a) and colon (RKO, RKO-E6) cancer cells. 3-AP treatment significantly enhanced radiation-related cytotoxicity in cervical and colon cancer cells. 3-AP treatment significantly decreased RNR activity, caused prolonged radiation-induced DNA damage, and resulted in an extended G1/S-phase cell cycle arrest in all cell lines. Similar effects were observed in both RKO and RKO-E6 cells, suggesting a p53-independent mechanism of radiosensitization. We conclude that inhibition of ribonucleotide reductase by 3-AP enhances radiation-mediated cytotoxicity independent of p53 regulation by impairing repair processes that rely on deoxyribonucleotide production, thereby substantially increasing the radiation sensitivity of human cancers.

Kunos, Charles A.; Chiu, Song-mao; Pink, John; Kinsella, Timothy J.

2009-01-01

269

Engineered mutated glutaredoxins mimicking peculiar plant class III glutaredoxins bind iron-sulfur centers and possess reductase activity.  

PubMed

In order to gather biochemical information about class III glutaredoxins (CCxC/S active sites), the active sites of two poplar class I glutaredoxins, GrxC1 and C4, CGYC and CPYC, respectively, were transformed into CCMC or CCMS. All the recombinant mutated proteins bind [2Fe-2S] centers into holodimers, whereas monomeric apoforms possess glutathione-dependent reductase activity. The functionally important, hydrophobic GALWL C-terminal end, found in most class III glutaredoxins, prevents expression in Escherichia coli. Changing the C-terminal end of GrxS7.2, a genuine class III glutaredoxin, allowed purifying some holoproteins. These properties are discussed considering the documented function of class III glutaredoxins in development. PMID:21094149

Couturier, Jérémy; Didierjean, Claude; Jacquot, Jean-Pierre; Rouhier, Nicolas

2010-11-19

270

Association of the 677C -->T polymorphism in the MTHFR gene with colorectal cancer in Mexican patients.  

PubMed

The 5,10-methyl-tetrahydrofolate reductase (MTHFR) enzyme plays a critical role in folate and homocysteine metabolism, and its gene, MTHFR, displays common genetic polymorphisms that influence its activity. Clinical implications of MTHFR polymorphisms have been reported for several diseases, including a variety of solid tumors such as colorectal cancer (CRC). Here, the role of the 677C -->T polymorphism of MTHFR was evaluated by genotyping 369 patients and 170 healthy controls from the Mexican population. The observed genotype frequencies for the controls and patients, respectively, were: 18.8% and 32% for 677TT; 34.7% and 34% for 677CC; 46.4% and 34% for 677CT. The odds ratio (OR) was 2.0 (95% confidence intervals CI; 1.3-3.3) (p<0.05). The data suggested that the 677C -->T polymorphism in MTHFR contributes significantly to the risk of CRC susceptibility in the Mexican population. PMID:19487547

Gallegos-Arreola, M P; García-Ortiz, J E; Figuera, L E; Puebla-Pérez, A M; Morgan-Villela, G; Zúńiga-González, G M

271

MTHFR 677 C>T and 1298 A>C polymorphisms and the age of onset of colorectal cancer in hereditary nonpolyposis colorectal cancer  

PubMed Central

Hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome is characterized by inactivating germline mutations in DNA mismatch repair genes resulting in an increased risk of developing an epithelial malignancy. There is considerable variability in disease expression observed in this syndrome, which is thought to be due to a combination of genetic and environmental factors. Alterations in the kinetics of methylene tetrahydrofolate reductase (MTHFR) due to the presence of polymorphisms in the MTHFR gene have been associated with an increased risk of colorectal cancer (CRC). Two common single nucleotide polymorphisms (SNPs) located within the MTHFR gene, 677 C>T and 1298 A>C, that alter the function of the encoded protein have been the focus of many studies on CRC risk outside the context of an inherited predisposition to disease. In this report, a total of 417 HNPCC participants were genotyped for the 677 C>T and 1298 A>C SNPs to determine whether there exists an association with the age of disease onset of CRC. Genotyping of both SNPs was performed by TaqMan® assay technology. Associations in disease risk were further investigated using Kaplan–Meier survival analysis and Cox hazard regression. The average ages of disease diagnosis were found to be different between individuals harbouring either one of the MTHFR polymorphisms. Both Kaplan–Meier and Cox hazard regression analyses revealed a more complex relationship between the two polymorphisms and the age of CRC onset. The Kaplan–Meier survival analysis revealed that compound heterozygotes for the two SNPs developed CRC 10 years later compared with those carrying only wild-type alleles.

Reeves, Stuart G; Meldrum, Cliff; Groombridge, Claire; Spigelman, Allan D; Suchy, Janina; Kurzawski, Grzegorz; Lubinski, Jan; McElduff, Patrick; Scott, Rodney J

2009-01-01

272

MTHFR 677 C>T and 1298 A>C polymorphisms and the age of onset of colorectal cancer in hereditary nonpolyposis colorectal cancer.  

PubMed

Hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome is characterized by inactivating germline mutations in DNA mismatch repair genes resulting in an increased risk of developing an epithelial malignancy. There is considerable variability in disease expression observed in this syndrome, which is thought to be due to a combination of genetic and environmental factors. Alterations in the kinetics of methylene tetrahydrofolate reductase (MTHFR) due to the presence of polymorphisms in the MTHFR gene have been associated with an increased risk of colorectal cancer (CRC). Two common single nucleotide polymorphisms (SNPs) located within the MTHFR gene, 677 C>T and 1298 A>C, that alter the function of the encoded protein have been the focus of many studies on CRC risk outside the context of an inherited predisposition to disease. In this report, a total of 417 HNPCC participants were genotyped for the 677 C>T and 1298 A>C SNPs to determine whether there exists an association with the age of disease onset of CRC. Genotyping of both SNPs was performed by TaqMan(R) assay technology. Associations in disease risk were further investigated using Kaplan-Meier survival analysis and Cox hazard regression. The average ages of disease diagnosis were found to be different between individuals harbouring either one of the MTHFR polymorphisms. Both Kaplan-Meier and Cox hazard regression analyses revealed a more complex relationship between the two polymorphisms and the age of CRC onset. The Kaplan-Meier survival analysis revealed that compound heterozygotes for the two SNPs developed CRC 10 years later compared with those carrying only wild-type alleles. PMID:19156174

Reeves, Stuart G; Meldrum, Cliff; Groombridge, Claire; Spigelman, Allan D; Suchy, Janina; Kurzawski, Grzegorz; Lubinski, Jan; McElduff, Patrick; Scott, Rodney J

2009-01-21

273

Molecular genetics of methylenetetrahydrofolate reductase deficiency.  

PubMed

In severe MTHFR deficiency with neonatal or adolescent onset, 9 rare mutations have been identified. In mild MTHFR deficiency with thermolabile enzyme, a single common mutation (an alanine-to-valine substitution) is involved, but a genetic-nutrient interactive effect is required to produce mild hyperhomocysteinaemia. This interactive effect has been proposed to be a risk factor for arteriosclerosis and for neural-tube defects. Large-scale studies are required for confirmation of the role of MTHFR in these multifactorial processes as well as to assess its role in other folate-dependent disorders. PMID:8892013

Rozen, R

1996-01-01

274

Polymorphisms in the Methylenetetrahydrofolate Reductase Gene Are Associated with Susceptibility to Acute Leukemia in Adults  

Microsoft Academic Search

Reduction of 5,10-methylenetetrahydrofolate (methyleneTHF), a donor for methylating dUMP to dTMP in DNA synthesis, to 5-methyltetrahydrofolate (methylTHF), the primary methyl donor for methionine synthesis, is catalyzed by 5,10-methylenetetrahydrofolate reductase (MTHFR). A common 677 C--> T polymorphism in the MTHFR gene results in thermolability and reduced MTHFR activity that decreases the pool of methylTHF and increases the pool of methyleneTHF. Recently,

Christine F. Skibola; Martyn T. Smith; Eleanor Kane; Eve Roman; Sara Rollinson; Raymond A. Cartwright; Gareth Morgan

1999-01-01

275

Methotrexate toxicity and efficacy during the consolidation phase in paediatric acute lymphoblastic leukaemia and MTHFR polymorphisms as pharmacogenetic determinants  

Microsoft Academic Search

Purpose  Folate-metabolizing single-nucleotide polymorphisms (SNPs) are emerging as important pharmacogenetic prognostic determinants\\u000a of the response to chemotherapy. With high doses of methotrexate (MTX) in the consolidation phase, methylenetetrahydrofolate\\u000a reductase (MTHFR) polymorphisms could be potential modulators of the therapeutic response to antifolate chemotherapeutics\\u000a in identifying a possible correlation with the outcome. This study aims to analyse the potential role of the MTHFR

Velia D’Angelo; Maria Ramaglia; Adriana Iannotta; Stefania Crisci; Paolo Indolfi; Matteo Francese; Maria Carmen Affinita; Giulia Pecoraro; Addolorata Napolitano; Claudia Fusco; Matilde Oreste; Cristiana Indolfi; Fiorina Casale

276

Screening for C677T and A1298C MTHFR polymorphisms in patients with epilepsy and risk of hyperhomocysteinemia  

Microsoft Academic Search

Hyperhomocysteinemia can result from decreased methylenetetrahydrofolate reductase (MTHFR) enzyme activity, owing to genetic\\u000a polymorphisms and\\/or inadequate folate intake. This study was aimed at investigating the prevalence of C677T and A1298C MTHFR\\u000a polymorphisms, and their impact on hyperhomocysteinemia in 95 epileptic patients and 98 controls. Double gradient-denaturing\\u000a gradient gel electrophoresis screening revealed that the frequency of T677 polymorphic allele was similar

D. Caccamo; S. Condello; G. Gorgone; G. Crisafulli; V. Belcastro; S. Gennaro; P. Striano; F. Pisani; R. Ientile

2004-01-01

277

Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia  

Microsoft Academic Search

The central role of 5,10-methylenetetrahydrofolate reductase (MTHFR) and methylenetetrahydrofolate dehydrogenase (MTHFD1) in folate metabolism renders polymorphisms in genes encoding these enzymes potential modulators of therapeutic response to antifolate chemotherapeutics. The analysis of 201 children treated with methotrexate for childhood acute lymphoblastic leukemia (ALL) showed that patients with either the MTHFR T677A1298 haplotype or MTHFD1 A1958 variant had a lower probability

M Krajinovic; É Lemieux-Blanchard; S Chiasson; M Primeau; I Costea; A Moghrabi

2004-01-01

278

MTHFR genotype and colorectal adenoma recurrence: data from a double-blind placebo-controlled clinical trial  

Microsoft Academic Search

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism. We assessed the association between two common MTHFR variants, 677C>T and 1298A>C, and adenoma recurrence in the context of a randomized double- blind clinical trial of aspirin use and folate supplementation. We used generalized linear regression to estimate risk ratios and 95% confidence intervals (95% CI) for recurrence, adjusting for

A. Joan Levine; Kristin Wallace; Shirley Tsang; Robert W. Haile; Fred Saibil; Dennis J. Ahnen; Bernard F. Cole; Elizabeth L. Barry; David Munroe; Iqbal U. Ali; Per M. Ueland; John A. Baron

2008-01-01

279

Evaluation of the MTHFR A1298C variant in leukoaraiosis.  

PubMed

Vascular demyelinization of the white matter of the brain is referred to as leukoaraiosis (LA). This very frequent entity is associated with a cognitive decline, thereby resulting in a deteriorating quality of life. Besides poorly controlled hypertension and aging, its development is reported to be associated with an elevated serum homocysteine level. Although the methylenetetrahydrofolate reductase (MTHFR) C677T genetic variant is associated with an elevated serum homocysteine level, it has not been proved to be an independent risk factor for LA. The aim of the present study was to examine whether the MTHFR A1298C genetic variant, which is also believed to be unfavorable, is associated with the presence of LA. The clinical and genetic data on 198 LA patients and 235 neuroimaging alteration-free controls were analyzed. The presence of the A1298C or the 1298CC variant was calculated to be a risk factor for LA, as compared with the absence of both of them. The clustering of the heterozygous A1298C and C677T variants was proved to involve the risk of LA. Our results suggest that the MTHFR A1298C variant confers an independent genetic risk of LA, and this pathological role may be amplified by the MTHFR C677T variant. PMID:21845428

Szolnoki, Zoltan; Szaniszlo, Istvan; Szekeres, Marta; Hitri, Krisztina; Kondacs, Andras; Mandi, Yvette; Nedo, Erika; Somogyvari, Ferenc

2011-08-16

280

Population- and Family-Based Studies Associate the "MTHFR" Gene with Idiopathic Autism in Simplex Families  

ERIC Educational Resources Information Center

|Two methylenetetrahydrofolate reductase gene ("MTHFR") functional polymorphisms were studied in 205 North American simplex (SPX) and 307 multiplex (MPX) families having one or more children with an autism spectrum disorder. Case-control comparisons revealed a significantly higher frequency of the low-activity 677T allele, higher prevalence of the…

Liu, Xudong; Solehdin, Fatima; Cohen, Ira L.; Gonzalez, Maripaz G.; Jenkins, Edmund C.; Lewis, M. E. Suzanne; Holden, Jeanette J. A.

2011-01-01

281

Methylenetetrahydrofolate reductase gene, homocysteine and coronary artery disease: the A1298C polymorphism does matter. Inferences from a case study (Madeira, Portugal).  

PubMed

Elevated levels of plasma homocysteine, an independent risk factor and a strong predictor of mortality in patients with coronary artery disease (CAD), can result from nutritional deficiencies or genetic errors, including methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms. The contribution of these polymorphisms in the development of CAD remains controversial. We analysed the impact of MTHFR C677T and A1298C on fasting homocysteine and CAD in 298 CAD patients proved by angiography and 510 control subjects from the Island of Madeira (Portugal). After adjustment for other risk factors, plasma homocysteine remained independently correlated with CAD. Serum homocysteine was significantly higher in individuals with 677TT and 1298AA genotypes. There was no difference in the distribution of MTHFR677 genotypes between cases and controls but a significant increase in 1298AA prevalence was found in CAD patients. In spite of the clear effect of C677T mutation on elevated homocysteine levels we only found an association between 1298AA genotype and CAD in this population. The simultaneous presence of 677CT and 1298AA genotypes provides a significant risk of developing the disease, while the 1298AC genotype, combined with 677CC, shows a significant trend towards a decrease in CAD occurrence. The data shows an independent association between elevated levels of homocysteine and CAD. Both MTHFR polymorphisms are associated with increased fasting homocysteine (677TT and 1298AA genotypes), but only the 1298AA variant shows an increased prevalence in CAD group. Odds ratio seem to indicate that individuals with the MTHFR 1298AA genotype and the 677CT/1298AA compound genotype had a 1.6-fold increased risk for developing CAD suggesting a possible association of MTHFR polymorphisms with the risk of CAD in Madeira population. PMID:18384842

Freitas, Ana I; Mendonça, Isabel; Guerra, Graça; Brión, Maria; Reis, Roberto P; Carracedo, Angel; Brehm, António

2008-04-01

282

MICE DEFICIENT IN METHYLENETETRAHYDROFOLATE REDUCTASE EXHIBIT TISSUE-SPECIFIC REGULATION OF FOLATE METABOLISM  

Technology Transfer Automated Retrieval System (TEKTRAN)

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate (5-methylTHF), which is used for homocysteine remethylation to methionine, the precursor of S-adenosylmethionine (SAM). Impairment of MTHFR will increase homocysteine levels and compromise SAM-dependent m...

283

Mutations in the Antifolate-Resistance-Associated Genes Dihydrofolate Reductase and Dihydropteroate Synthase in Plasmodium vivax Isolates from Malaria-Endemic Countries  

PubMed Central

Parasite dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) are known target enzymes of antifolate drugs used for the treatment and prophylaxis of persons with malaria. We sequenced the Plasmodium vivax dihydrofolate reductase (pvdhfr) and dihydropteroate synthase (pvdhps) genes to examine the prevalence and extent of point mutations in isolates from malaria-endemic countries. Double mutations (S58R and S117N) or quadruple mutations (F57L/I, S58R, T61M, and S117T) in the pvdhfr gene were found in isolates from Thailand (96.4%) and Myanmar (71.4%), but in only one isolate (1.0%) from Korea, where sulfadoxine-pyrimethamine has never been used. The pvdhfr point mutations correlated strongly with the pvdhps point mutations and ranged from single to triple mutations (S382A, A383G, and A553G), among isolates from Thailand, Myanmar, and Korea. These findings suggests that the prevalence of mutations in pvdhfr and pvdhps in P. vivax isolates from different malaria-endemic countries is associated with selection pressure imposed by sulfadoxine-pyrimethamine.

Lu, Feng; Lim, Chae Seung; Nam, Deok Hwa; Kim, Kwonkee; Lin, Khin; Kim, Tong-Soo; Lee, Hyeong-Woo; Chen, Jun-Hu; Wang, Yue; Sattabongkot, Jetsumon; Han, Eun-Taek

2010-01-01

284

Postnatal cerebellar defects in mice deficient in methylenetetrahydrofolate reductase.  

PubMed

Patients with severe deficiency of methylenetetrahydrofolate reductase (MTHFR) suffer from a wide variety of neurological problems, which can begin in the neonatal period. MTHFR is a critical enzyme in folate metabolism; the product of the MTHFR reaction, 5-methyltetrahydrofolate, is required for homocysteine remethylation to methionine and synthesis of S-adenosylmethionine (SAM). To understand the mechanisms by which MTHFR deficiency leads to significant neuropathology, we examined early postnatal brain development in mice with a homozygous knockout of the Mthfr gene. These mice displayed a dramatically reduced size of the cerebellum and cerebral cortex, with enlarged lateral ventricles. Mthfr deficiency affected granule cell maturation, but not neurogenesis. Depletion of external granule cells and disorganization of Purkinje cells were mainly confined to the anterior lobules of mutant cerebella. Decreased cellular proliferation and increased cell death contributed to the granule cell loss. Reduced expression of Engrailed-2 (En2), Reelin (Reln) and inositol 1,4,5-triphosphate receptor type 1 (Itpr1) genes was observed in the cerebellum. Supplementation of Mthfr(+/-) dams with an alternate methyl donor, betaine, reduced cerebellar abnormalities in the Mthfr(-/-) pups. Our findings suggest that MTHFR plays a role in cerebellar patterning, possibly through effects on proliferation or apoptosis. PMID:15979267

Chen, Zhoutao; Schwahn, Bernd C; Wu, Qing; He, Xinying; Rozen, Rima

2005-08-01

285

Mutational analysis of the yeast coenzyme QH2-cytochrome c reductase complex.  

PubMed

The synthesis of cytochrome b in yeast depends on the expression of both mitochondrial and nuclear gene products that act at the level of processing of the pre-mRNA, translation of the mRNA, and maturation of the apoprotein during its assembly with the nuclear-encoded subunits of coenzyme QH2-cytochrome c reductase. Previous studies indicated one of the nuclear genes (CBP2) to code for a protein that is needed for the excision of the terminal intervening sequence from the pre-mRNA. We show here that the intervening sequence can promote its own excision in the presence of high concentrations of magnesium ion (50 mM), but that at physiological concentrations of the divalent cation (5 mM), the splicing reaction requires the presence of the CBP2-encoded product. These results provide strong evidence for a direct participation of the protein in splicing, most likely in stabilizing a splicing competent structure in the RNA. The conversion of apocytochrome b to the functional cytochrome has been examined in mutants lacking one or multiple structural subunits of the coenzyme QH2-cytochrome c reductase complex. Based on the phenotypes of the different mutants studied, the following have been concluded. (i) The assembly of catalytically active enzyme requires the synthesis of all except the 17 kDa subunit. (ii) Membrane insertion of the individual subunits is not contingent on protein-protein interactions. (iii) Assembly of the subunits occurs in the lipid bilayer following their insertion. (iv) The attachment of haem to apocytochrome b is a late event in assembly after an intermediate complex of the structural subunits has been formed. This complex minimally is composed of apocytochrome b, the non haem iron protein and all the non-catalytic subunits except for the 17 kDa core 3 subunit. PMID:2901760

Tzagoloff, A; Crivellone, M D; Gampel, A; Muroff, I; Nishikimi, M; Wu, M

1988-05-31

286

Natural mutations lead to enhanced proteasomal degradation of human Ncb5or, a novel flavoheme reductase.  

PubMed

NADH cytochrome b5 oxidoreductase (Ncb5or) protects ?-cells against oxidative stress and lipotoxicity. The predominant phenotype of lean Ncb5or-null mouse is insulin-dependent diabetes due to ?-cell death. This suggests the putative role of NCB5OR polymorphism in human diabetes. Therefore, we aimed to investigate the effect of natural missense mutations on the expression of human NCB5OR. Protein and mRNA levels of five non-synonymous coding variants were analyzed in transfected HEK293 and HepG2 cells. Although the mRNA levels were only slightly affected by the mutations, the amount of Ncb5or protein was largely reduced upon two Glu to Gly replacements in the third exon (p.E87G, p.E93G). These two mutations remarkably and synergistically shortened the half-life of Ncb5or and their effect could be attenuated by proteasome inhibitors. Our results strongly indicate that p.E87G, p.E93G mutations lead to enhanced proteasomal degradation due to manifest conformational alterations in the b5 domain. These data provide first evidence for natural mutations in NCB5OR gene resulting in decreased protein levels and hence having potential implications in human pathology. PMID:23523930

Kálmán, Fanni S; Lizák, Beáta; Nagy, Szilvia K; Mészáros, Tamás; Zámbó, Veronika; Mandl, József; Csala, Miklós; Kereszturi, Eva

2013-03-19

287

5,10 Methylenetetrahydrofolate reductase genetic polymorphism as a risk factor for neural tube defects  

SciTech Connect

Persons with a thermolabile form of the enzyme 5,10 methylenetetrahydrofolate reductase (MTHFR) have reduced enzyme activity and increased plasma homocysteine which can be lowered by supplemental folic acid. Thermolability of the enzyme has recently been shown to be caused by a common mutation (677C{sup {r_arrow}}T) in the MTHFR gene. We studied 41 fibroblast cultures from NTD-affected fetuses and compared their genotypes with those of 109 blood specimens from individuals in the general population. 677C{sup {r_arrow}}T homozygosity was associated with a 7.2 fold increased risk for NTDs (95% confidence interval: 1.8-30.3; p value: 0.001). These preliminary data suggest that the 677C{sup {r_arrow}}T polymorphism of the MTHFR gene is a risk factor for spina bifida and anencephaly that may provide a partial biologic explanation for why folic acid prevents these types of NTD. 13 refs., 1 fig., 1 tab.

Ou, C.Y.; Brown, V.K.; Khoury, M.J. [Centers for Disease Control and Prevention, Atlanta, GA (United States)] [and others

1996-06-28

288

Characterization of disease-related 5beta-reductase (AKR1D1) mutations reveals their potential to cause bile acid deficiency.  

PubMed

Bile acid deficiency is a serious syndrome in newborns that can result in death if untreated. 5beta-Reductase deficiency is one form of bile acid deficiency and is characterized by dramatically decreased levels of physiologically active 5beta-reduced bile acids. AKR1D1 (aldo-keto reductase 1D1) is the only known human enzyme that stereo-specifically reduces the Delta(4) double bond in 3-keto steroids and sterols to yield the 5beta-hydrogenated product. Analysis of the AKR1D1 gene in five patients with 5beta-reductase deficiency revealed five different mutations resulting in an amino acid substitution in the protein. To investigate a causal role for these observed point mutations in AKR1D1 in 5beta-reductase deficiency, we characterized their effect on enzymatic properties. Attempts to purify mutant enzymes by overexpression in Escherichia coli only yielded sufficient amounts of the P133R mutant for further characterization. This enzyme displayed a highly reduced K(m) and V(max) reminiscent of uncompetitive kinetics with 4-cholesten-7alpha-ol-3-one as substrate. In addition, this mutant displayed no change in cofactor affinity but was more thermolabile in the absence of NADPH as judged by CD spectroscopy. All mutants were compared following expression in HEK 293 cells. Although these enzymes were equally expressed based on mRNA levels, protein expression and functional activity were dramatically reduced. Cycloheximide treatment also revealed that several of the expressed mutants were less stable. Our findings show that the reported mutations in AKR1D1 in patients with 5beta-reductase lead to significantly decreased levels of active enzyme and could be causal in the development of bile acid deficiency syndrome. PMID:20522910

Drury, Jason E; Mindnich, Rebekka; Penning, Trevor M

2010-06-03

289

Genetic polymorphism of MTHFR G1793A in Chinese populations.  

PubMed

5,10-methylenetetrahydrofolate reductase (MTHFR) is an important enzyme in folate metabolism. A novel polymorphic site in MTHFR (G1793A) could influence the homocysteine levels and was first described in 2002. Investigations revealed that this allele was associated with susceptibility to several cancers, but its distribution around the world was not adequate. To study the prevalence of the mutant frequency in Chinese populations, 923 healthy individuals from 13 Chinese populations distributing widely from north to south were collected. DNA samples were isolated from peripheral blood samples and genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), with the digestion of restriction endonuclease BsrBI. Of the 923 individuals, 82.1% were GG homozygous, 17.2% were GA heterozygous and 0.7% were AA homozygous. The frequency of the MTHFR 1793A allele in all tested individuals was 9.3%, which was slightly lower than indicated by HapMap (10%, Beiing Han, 45 samples). The frequencies of A allele were generally higher in southern China than that in northern China, and the frequencies had significant variance in 13 Chinese populations (X2 = 26.315, P = 0.010). Summarizing of the MTHFR G1793A allele polymorphism, including control groups in the case-control studies, we found only 20 normal peoples with AA homozygous (7 Chineses, 1 Caucasian, 2 Java Indonesias, 2 non-Hispanic whites, 6 Irish women, 2 Indians). The Java Indonesias and Ashkenzai Jevish had the highest (26.6%) and the lowest (1.3%) 1793A frequency, respectively. Together with our previous data, the MTHFR G1793A polymorphism was in linkage disequilibrium with both C677T and A1298C polymorphism sites in Chinese population, but not as strong as presented by HapMap. PMID:18409008

Mao, Renfang; Fan, Yihui; Chen, Feng; Fu, Songbin

2008-01-01

290

Synergistic effects of the MTHFR C677T and A1298C polymorphisms on the increased risk of micro- and macro-albuminuria and progression of diabetic nephropathy among Iranians with type 2 diabetes mellitus  

Microsoft Academic Search

ObjectivesTo find whether polymorphisms of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C are risk factors for diabetic nephropathy (DN) among type 2 diabetes mellitus (T2DM) patients from Western Iran.

Mehrali Rahimi; Ali Hasanvand; Zohreh Rahimi; Asad Vaisi-Raygani; Hadi Mozafari; Mansour Rezaei; Javad Zargooshi; Farid Najafi; Ebrahim Shakiba

2010-01-01

291

Targeted Mutations of Bacillus anthracis Dihydrofolate Reductase Condense Complex Structure-Activity Relationships  

SciTech Connect

Several antifolates, including trimethoprim (TMP) and a series of propargyl-linked analogues, bind dihydrofolate reductase from Bacillus anthracis (BaDHFR) with lower affinity than is typical in other bacterial species. To guide lead optimization for BaDHFR, we explored a new approach to determine structure-activity relationships whereby the enzyme is altered and the analogues remain constant, essentially reversing the standard experimental design. Active site mutants of the enzyme, Ba(F96I)DHFR and Ba(Y102F)DHFR, were created and evaluated with enzyme inhibition assays and crystal structures. The affinities of the antifolates increase up to 60-fold with the Y102F mutant, suggesting that interactions with Tyr 102 are critical for affinity. Crystal structures of the enzymes bound to TMP and propargyl-linked inhibitors reveal the basis of TMP resistance and illuminate the influence of Tyr 102 on the lipophilic linker between the pyrimidine and aryl rings. Two new inhibitors test and validate these conclusions and show the value of the technique for providing new directions during lead optimization.

J Beierlein; N Karri; A Anderson

2011-12-31

292

Association between MTHFR polymorphism (C677T) with nonfamilial colorectal cancer.  

PubMed

The enzyme 5,10-methylene-tetrahydrofolate reductase (MTHFR) is linked to DNA methylation, synthesis, and repair. C677T is one of the most important polymorphisms in the MTHFR gene. The single nucleotide polymorphism C677T has been found to be associated with decreased enzyme activity and plasma folate, and thus may play a crucial role in the etiology of colorectal cancer. This decrease was observable in people with either high or low folate status. We aimed to test the hypothesis that the C677T genotype is involved in colorectal cancer. Using pyrosequencing, we analyzed the MTHFR genotypes in 234 colorectal cancer patients and 257 matched controls. We examined the polymorphisms in MTHFR and folate intake in relation to risk of colon cancer in an Iranian population-based case-control study. Our finding revealed that the CC, CT, and TT genotypes of MTHFR among the colorectal cancer patients were 50%, 29.1%, and 20.9%, respectively. On the other hand, we could find 29.5% of 677CC, 46% of 677CT and 24.5% of 677TT in the controls. A decreased risk of colon cancer for participants with wild-type genotype was observed. Interestingly, this association was stronger at higher levels of folate intake. Our study corroborates previous findings of an inverse association of the MTHFR 677TT genotype with colorectal cancer, in particular at high levels of folate. PMID:20066895

Haghighi, Mahdi Montazer; Radpour, Ramin; Mahmoudi, Touraj; Mohebbi, Seyed Reza; Vahedi, Mohsen; Zali, Mohammad Reza

2009-01-01

293

MTHFR genotype and colorectal adenoma recurrence: data from a double blind placebo controlled clinical trial  

PubMed Central

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism. We ssessed the association between two common MTHFR variants, 677C>T and 1298A>C, and adenoma recurrence in the context of a randomized double blind clinical trial of aspirin use and folate supplementation. We used generalized linear regression to estimate risk ratios and 95% CIs for recurrence, adjusting for age, sex, clinical center, follow-up time, and treatment status. Neither MTHFR polymorphism was associated with overall or advanced adenoma recurrence. Compared to those with 2 wild type alleles, the relative risk for advanced adenoma was 0.75 (95% CI 0.36 to 1.55), for the MTHFR 677 TT genotype and 1.16 (95% CI 0.58–2.33) for the MTHFR 1298 CC genotype. The effect of folate supplementation on recurrence risk did not differ by genotype. Our findings indicate that MTHFR genotype does not change adenoma risk in a manner similar to its effect on colorectal cancer, and does not modify the effect of folate supplementation on metachronous adenoma risk.

Levine, A. Joan; Wallace, Kristin; Tsang, Shirley; Haile, Robert W.; Saibil, Fred; Ahnen, Dennis; Cole, Bernard F.; Barry, Elizabeth L.; Munroe, David J; Ali, Iqbal U; Ueland, Per; Baron, John A.

2009-01-01

294

Association of the MTHFR A1298C variant with unexplained severe male infertility.  

PubMed

The methylenetetrahydrofolate reductase (MTHFR) gene is one of the main regulatory enzymes involved in folate metabolism, DNA synthesis and remethylation reactions. The influence of MTHFR variants on male infertility is not completely understood. The objective of this study was to analyze the distribution of the MTHFR C677T and A1298C variants using PCR-Restriction Fragment Length Polymorphism (RFLP) in a case group consisting of 344 men with unexplained reduced sperm counts compared to 617 ancestry-matched fertile or normozoospermic controls. The Chi square test was used to analyze the genotype distributions of MTHFR polymorphisms. Our data indicated a lack of association of the C677T variant with infertility. However, the homozygous (C/C) A1298C polymorphism of the MTHFR gene was present at a statistically high significance in severe oligozoospermia group compared with controls (OR?=?3.372, 95% confidence interval CI?=?1.27-8.238; p?=?0.01431). The genotype distribution of the A1298C variants showed significant deviation from the expected Hardy-Weinberg equilibrium, suggesting that purifying selection may be acting on the 1298CC genotype. Further studies are necessary to determine the influence of the environment, especially the consumption of diet folate on sperm counts of men with different MTHFR variants. PMID:22457816

Eloualid, Abdelmajid; Abidi, Omar; Charif, Majida; El Houate, Brahim; Benrahma, Houda; Louanjli, Noureddine; Chadli, Elbakkay; Ajjemami, Maria; Barakat, Abdelhamid; Bashamboo, Anu; McElreavey, Ken; Rhaissi, Houria; Rouba, Hassan

2012-03-23

295

Methylenetetrahydrofolate reductase deficiency in a patient with phenotypic findings of Angelman syndrome.  

PubMed

Deficiency of methylenetetrahydrofolate reductase (MTHFR) is associated with a variable phenotype that includes mental retardation, gait abnormalities, and seizures. Many of the same clinical findings are also seen in patients with Angelman syndrome. We report on a patient with MTHFR deficiency who was initially diagnosed as having Angelman syndrome. This case illustrates that MTHFR deficiency can mimic the phenotype of Angelman syndrome and that MTHFR deficiency should be excluded in patients with manifestations of Angelman syndrome whose molecular studies of chromosome 15 are normal. PMID:9605586

Arn, P H; Williams, C A; Zori, R T; Driscoll, D J; Rosenblatt, D S

1998-05-18

296

Mutation of the Bacillus subtilis alkyl hydroperoxide reductase (ahpCF) operon reveals compensatory interactions among hydrogen peroxide stress genes.  

PubMed Central

In Bacillus subtilis, hydrogen peroxide induces the synthesis of catalase (KatA), alkyl hydroperoxide reductase (AhpCF), and a DNA-binding protein of the Dps family (MrgA). KatA, AhpCF, heme biosynthesis enzymes, and MrgA are also induced upon entry into stationary phase under conditions of iron and manganese limitation. In an effort to define the peroxide regulon repressor, PerR, we used mini-Tn10 mutagenesis to identify loci affecting the regulation of mrgA. From this screen, we isolated two mini-Tn10 insertions in ahpC, the gene encoding the small subunit of AhpCF, that increase the transcription of mrgA-lacZ even in iron-supplemented minimal medium. Indeed, these ahpC::Tn10 insertions lead to elevated expression from all peroxide regulon promoters, including those for mrgA, katA, hemAXCDBL, and ahpCF. As a result, the ahpC::Tn10 mutants display an increased resistance to H2O2. The ahpCF promoter region contains three sequences similar to the peroxide regulon consensus operator (per box). We demonstrate that the ability of ahpC::Tn10 mutations to derepress mrgA requires aerobic growth. In contrast, a second distinct trans-acting regulatory mutation bypasses this requirement for aerobic growth. Since the peroxide regulon is activated in the absence of AhpCF, which degrades alkyl hydroperoxides, we propose that organic hydroperoxides may be physiologically relevant inducers in vivo.

Bsat, N; Chen, L; Helmann, J D

1996-01-01

297

Methylenetetrahydrofolate reductase deficiency: prenatal diagnosis and family studies.  

PubMed

Prenatal diagnosis of methylenetetrahydrofolate reductase (MTHFR) deficiency and family studies were performed because of a severely affected first child in this family. The fetus at risk was found to be heterozygous as confirmed by the enzymatic activity assay performed several times after birth. In the father, MTHFR activity was normal in lymphocytes and decreased in fibroblasts, whereas in the asymptomatic mother, the activity was not detectable in fibroblasts and was very low in lymphocytes. The absence of any clinical symptoms in the mother despite a clear MTHFR deficiency and hyperhomocystinemia emphasizes the heterogeneity of this disease. PMID:8183835

Marquet, J; Chadefaux, B; Bonnefont, J P; Saudubray, J M; Zittoun, J

1994-01-01

298

A new strategy to produce a defensin: stable production of mutated NP-1 in nitrate reductase-deficient Chlorella ellipsoidea.  

PubMed

Defensins are small cationic peptides that could be used as the potential substitute for antibiotics. However, there is no efficient method for producing defensins. In this study, we developed a new strategy to produce defensin in nitrate reductase (NR)-deficient C. ellipsoidea (nrm-4). We constructed a plant expression vector carrying mutated NP-1 gene (mNP-1), a mature ?-defensin NP-1 gene from rabbit with an additional initiator codon in the 5'-terminus, in which the selection markers were NptII and NR genes. We transferred mNP-1 into nrm-4 using electroporation and obtained many transgenic lines with high efficiency under selection chemicals G418 and NaNO(3). The mNP-1 was characterized using N-terminal sequencing after being isolated from transgenic lines. Excitingly, mNP-1 was produced at high levels (approximately 11.42 mg/l) even after 15 generations of continuous fermentation. In addition, mNP-1 had strong activity against Escherichia coli at 5 µg/ml. This research developed a new method for producing defensins using genetic engineering. PMID:23383016

Bai, Li-Li; Yin, Wei-Bo; Chen, Yu-Hong; Niu, Li-Li; Sun, Yong-Ru; Zhao, Shi-Min; Yang, Fu-Quan; Wang, Richard R-C; Wu, Qing; Zhang, Xiang-Qi; Hu, Zan-Min

2013-01-28

299

Methylenetetrahydrofolate reductase gene polymorphisms in 13 Chinese ethnic populations.  

PubMed

It has been shown that the polymorphisms of Methylenetetrahydrofolate reductase (MTHFR) gene are associated with susceptibility to several disorders including hyperhomocysteinemia, vascular disease, birth defect, and certain cancers, and exhibit great diversities among various populations. The aim of this study was to investigate the prevalence of two common non-synonymous single nucleotide polymorphisms (i.e., C677T and A1298C) at MTHFR gene in 13 Chinese populations. A total of 1015 healthy individuals from 13 populations distributed widely from north to south in China were studied. DNA samples were isolated from peripheral blood samples and genotyped using polymerase chain reaction-restriction fragment length polymorphism. For C677T polymorphism, the frequency in Chinese of CC homozygous was 42.4%; CT heterozygous was 49.8%; and TT homozygous was 7.9%. For A1298C, AA homozygous was 39.2%; AC heterozygous was 38.6%; and CC homozygous was 22.2%. The allelic frequency of 677T and 1298C was 32.8 and 41.5%, respectively, and each allele frequency had significant variance in 13 Chinese populations. The frequency of the 677T allele among southern populations was 30.7% compared to 38.0% among northeastern and 30.5% among northwestern populations. The difference was statistically significant (p < 0.01). The frequency of 1298C mutation in southerns was 58.9% whereas in northeasterns it was 24.0% and 37.6% in northwesterns. This was also statistically significant (p < 0.01). The MTHFR C677T and A1298C sites were in linkage disequilibrium in the Chinese population revealed by our data. PMID:18098118

Mao, Renfang; Fan, Yihui; Chen, Feng; Sun, Donglin; Bai, Jing; Fu, Songbin

2008-04-01

300

Methylenetetrahydrofolate reductase C677T and A1298C variants do not affect ongoing pregnancy rates following IVF  

Microsoft Academic Search

BACKGROUND: There is concern that IVF could compromise normal imprinting and methylation of DNA. Methyl- enetetrahydrofolate reductase (MTHFR) regulates the flow of folic acid-derived, one-carbon moieties for methylation and is critical to early embryonic development. Therefore, we hypothesized that common polymorphisms in MTHFR could associate with IVF outcome. METHODS: MTHFR C677T and A1298C polymorphism genotyping was per- formed on 374

A. T. Dobson; R. M. Davis; M. P. Rosen; S. Shen; P. F. Rinaudo; J. Chan; M. I. Cedars

2006-01-01

301

A1298C polymorphism in the MTHFR gene predisposes to cardiovascular risk in rheumatoid arthritis  

PubMed Central

Introduction We determined the contribution of the methylene tetrahydrofolate reductase (MTHFR) 677 C>T and 1298 A>C gene polymorphisms to the susceptibility to rheumatoid arthritis (RA). We also assessed whether these two MTHFR gene polymorphisms may be implicated in the development of cardiovascular (CV) events and subclinical atherosclerosis manifested by the presence of endothelial dysfunction, in a series of Spanish patients with RA. Methods Six hundred and twelve patients fulfilling the 1987 American College of Rheumatology classification criteria for RA, seen at the rheumatology outpatient clinics of Hospital Xeral-Calde, Lugo and Hospital San Carlos, Madrid, were studied. Patients and controls (n = 865) were genotyped using predesigned TaqMan SNP genotyping assays. Results No significant differences in allele or genotype frequencies for the MTHFR gene polymorphisms between RA patients and controls were found. Also, no association between the MTHFR 677 C>T polymorphism and CV events or endothelial dysfunction was observed. However, the MTHFR 1298 allele C frequency was increased in patients with CV events after 5 years (38.7% versus 30.3%; odds ratio = 1.45; 95% confidence interval = 1.00 to 2.10; P = 0.04) and 10 years (42.2% versus 31.0%; odds ratio = 1.62; 95% confidence interval = 1.08 to 2.43; P = 0.01) follow up. Moreover, patients carrying the MTHFR 1298 AC and CC genotypes had a significantly decreased flow-mediated endothelium-dependent vasodilatation (4.3 ± 3.9%) compared with those carrying the MTHFR 1298 AA genotype (6.5 ± 4.4%) (P = 0.005). Conclusions Our results show that the MTHFR 1298 A>C gene polymorphism confers an increased risk for subclinical atherosclerosis and CV events in patients with RA.

2010-01-01

302

Characterization of a pseudogene for murine methylenetetrahydrofolate reductase.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the major carbon donor in the remethylation of homocysteine to methionine. Mild MTHFR deficiency, due to a common variant at nucleotide 677, has been reported to influence risk for several disorders including cardiovascular disease, neural tube defects, pregnancy complications and cancer. In recent work, we characterized the complete cDNA and gene sequences in the human and mouse genes, which had previously been mapped to chromosomes 1 and 4, respectively. During the course of this work, we observed that PCR primers in exons 1 and 2 of Mthfr generated amplicons of the expected size for the normal Mthfr transcript, using both reverse-transcribed RNA and genomic DNA as templates. These findings alluded to the existence of a pseudogene in the murine genome. Here, we report the characterization of this pseudogene. The absence of intron 1, the partial retention of intron 2, the location of this gene on chromosome 5, and the presence of sequences unrelated to Mthfr at the 5' and 3' ends of the 1259 bp fragment are features that are indicative of a partially-processed pseudogene, that we have designated Mthfr-ps. A Mthfr-ps transcript was not detectable by sensitive RT-PCR using assays designed to simultaneously detect the authentic Mthfr transcript. The structure of this paralogous gene and the identification of a repeat sequence at the 3' end of this pseudogene suggest that it arose by retrotransposition of a mis-spliced Mthfr transcript. Investigations of the Mthfr gene should take into account the presence of the non-functional Mthfr-ps to avoid misinterpretation of results. PMID:14577615

Leclerc, Daniel; Darwich-Codore, Hiba; Rozen, Rima

2003-10-01

303

Polymorphism in Methylenetetrahydrofolate Reductase Gene: Its Impact on Plasma Homocysteine Levels and Carotid Atherosclerosis in ESRD Patients Receiving Hemodialysis  

Microsoft Academic Search

The methylenetetrahydrofolate reductase (MTHFR) gene polymorphism has been shown to be associated with cardiovascular disease in healthy subjects as well as in patients with end-stage renal disease (ESRD). In this study, we examined the allelic frequency and genotype distribution of the MTHFR gene in 151 Chinese ESRD patients receiving hemodialysis and 135 healthy controls. In addition, we investigated the relationship

Paik-Seong Lim; Wan-Ru Hung; Yau-Huei Wei

2001-01-01

304

MTHFR polymorphisms and risk of chronic lymphocytic leukemia.  

PubMed

Folate availability is critical for DNA integrity, required for the transfer of methyl groups in the biosynthesis of thymidilate. Reduction of 5,10-methylenetetrahydrofolate, a donor for methylating dUMP to dTMP in DNA synthesis, to 5-methyltetrahydrofolate, the primary methyl donor for methionine synthesis, is catalyzed by 5,10-methylenetetrahydrofolate reductase (MTHFR). The MTHFR polymorphisms C677T and A1298C have been shown in some studies to alter the risk of a range of different malignancies. We evaluated the role of the C677T and A1298C polymorphisms on chronic lymphocytic leukemia (CLL) risk by genotyping 832 patients and 886 healthy controls. The odds ratio of CLL associated with 677CT and 677TT genotypes were 1.02 [95% confidence interval (95% CI), 0.83-1.24] and 0.90 (95% CI, 0.66-1.24), respectively. The odds ratio of CLL associated with 1298AC and 1298CC genotypes were 0.97 (95% CI, 0.79-1.18) and 0.88 (95% CI, 0.62-1.24), respectively. This data indicate that the MTHFR polymorphisms C677T and A1298C do not significantly contribute to an inherited genetic susceptibility to CLL. PMID:15598791

Rudd, Matthew F; Sellick, Gabrielle S; Allinson, Ruth; Matutes, Estella; Catovsky, Daniel; Houlston, Richard S

2004-12-01

305

Methylenetetrahydrofolate reductase homozygosis and low-density lipoproteins in patients with genotype 1 chronic hepatitis C.  

PubMed

Methylenetetrahydrofolate reductase status, homocysteine and lipoproteins levels have been associated with severity of disease and both rapid and sustained virological response (SVR) in patients with genotype 1 chronic hepatitis C (CHC). We aimed to assess the association of homocysteine and MTHFR status with serum cholesterol levels and their potential links to both histological findings and virological response, in patients with genotype 1 hepatitis C virus (HCV). A total of 119 consecutive patients were evaluated by biopsy and metabolic measurements. A total of 103 healthy blood donors were used as controls. Serum homocysteine and MTHFR C677T mutation were also evaluated. All patients underwent antiviral therapy with PEG-IFN alfa-2a plus ribavirin. HCV-RNA was assessed at baseline, week 4, week 12, at the end of therapy and after 6 months of follow-up. Mean serum values of homocysteine were higher in patients than in controls (15.8 ± 5.8 ?g/L vs 12.5 ± 5.8 ?g/L; P < 0.001), with a similar CC, CT and TT MTHFR distribution (23.6%, 48.7% and 27.7% in G1-CHC vs 34%, 48.5% and 17.5% in controls; P = 0.14). In genotype 1, HCV MTHFR TT homozygosis was independently linked to higher LDL (OR 1.016; CI 1.002-1.031; P = 0.03), but not to homocysteine. No association were found between homocysteine, MTHFR and histological features or both rapid virological response (RVR) and SVR. Low cholesterol (OR 0.988, 95%CI 0.975-0.999, P = 0.04) was independently linked to severe fibrosis, and high LDL was the only independent positive predictors of both RVR and SVR (OR 1.036; 95%CI 1.017-1.055; P < 0.001; and OR 1.016; 95%CI 1.001-1.031; P = 0.04 respectively). In patients with genotype 1 hepatitis C, showing higher homocysteine serum levels than controls, MTHFR C677T homozygosis, via modulating cholesterol levels, could interfere with liver fibrosis and response to antiviral therapy. PMID:22676358

Petta, S; Bellia, C; Mazzola, A; Cabibi, D; Cammŕ, C; Caruso, A; Di Marco, V; Craxě, A; Ciaccio, M

2011-11-28

306

Intermittent encephalopathy, reversible nerve conduction slowing, and MRI evidence of cerebral white matter disease in methylenetetrahydrofolate reductase deficiency.  

PubMed

We describe a patient with methylenetetrahydrofolate reductase (MTHFR) deficiency in whom clinical and electrophysiologic fluctuations paralleled exacerbations of hyperhomocyst(e)inemia. MRI demonstrated abnormalities characteristic of a leukodystrophy. PMID:8309589

Walk, D; Kang, S S; Horwitz, A

1994-02-01

307

The MET13 Methylenetetrahydrofolate Reductase Gene Is Essential for Infection-Related Morphogenesis in the Rice Blast Fungus Magnaporthe oryzae  

PubMed Central

Methylenetetrahydrofolate reductases (MTHFRs) play a key role in the biosynthesis of methionine in both prokaryotic and eukaryotic organisms. In this study, we report the identification of a novel T-DNA-tagged mutant WH672 in the rice blast fungus Magnaporthe oryzae, which was defective in vegetative growth, conidiation and pathogenicity. Analysis of the mutation confirmed a single T-DNA insertion upstream of MET13, which encodes a 626-amino-acid protein encoding a MTHFR. Targeted gene deletion of MET13 resulted in mutants that were non-pathogenic and significantly impaired in aerial growth and melanin pigmentation. All phenotypes associated with ?met13 mutants could be overcome by addition of exogenous methionine. The M. oryzae genome contains a second predicted MTHFR-encoding gene, MET12. The deduced amino acid sequences of Met13 and Met12 share 32% identity. Interestingly, ?met12 mutants produced significantly less conidia compared with the isogenic wild-type strain and grew very poorly in the absence of methionine, but were fully pathogenic. Deletion of both genes resulted in ?met13?met12 mutants that showed similar phenotypes to single ?met13 mutants. Taken together, we conclude that the MTHFR gene, MET13, is essential for infection-related morphogenesis by the rice blast fungus M. oryzae.

Wang, Hong; Wang, Congcong; Li, Ya; Yue, Xiaofeng; Ma, Zhonghua; Talbot, Nicholas J.; Wang, Zhengyi

2013-01-01

308

The MET13 Methylenetetrahydrofolate Reductase Gene Is Essential for Infection-Related Morphogenesis in the Rice Blast Fungus Magnaporthe oryzae.  

PubMed

Methylenetetrahydrofolate reductases (MTHFRs) play a key role in the biosynthesis of methionine in both prokaryotic and eukaryotic organisms. In this study, we report the identification of a novel T-DNA-tagged mutant WH672 in the rice blast fungus Magnaporthe oryzae, which was defective in vegetative growth, conidiation and pathogenicity. Analysis of the mutation confirmed a single T-DNA insertion upstream of MET13, which encodes a 626-amino-acid protein encoding a MTHFR. Targeted gene deletion of MET13 resulted in mutants that were non-pathogenic and significantly impaired in aerial growth and melanin pigmentation. All phenotypes associated with ?met13 mutants could be overcome by addition of exogenous methionine. The M. oryzae genome contains a second predicted MTHFR-encoding gene, MET12. The deduced amino acid sequences of Met13 and Met12 share 32% identity. Interestingly, ?met12 mutants produced significantly less conidia compared with the isogenic wild-type strain and grew very poorly in the absence of methionine, but were fully pathogenic. Deletion of both genes resulted in ?met13?met12 mutants that showed similar phenotypes to single ?met13 mutants. Taken together, we conclude that the MTHFR gene, MET13, is essential for infection-related morphogenesis by the rice blast fungus M. oryzae. PMID:24116181

Yan, Xia; Que, Yawei; Wang, Hong; Wang, Congcong; Li, Ya; Yue, Xiaofeng; Ma, Zhonghua; Talbot, Nicholas J; Wang, Zhengyi

2013-10-07

309

Effects of the C677T and A1298C polymorphisms of the MTHFR gene on the genetic predisposition for diabetic nephropathy  

Microsoft Academic Search

Background. Methylenetetrahydrofolate reductase (MTHFR) is a regulatory enzyme of homocysteine metabolism. The C677T polymorphism of the MTHFR gene has been reported to be associated with elevated plasma homocysteine in patients with low folic acid intake. A recently reported second common poly- morphism, A1298C, may increase homocysteine, but only in individuals carryingthe T677 allele. This study aimed to investigate the influence

Dariusz Moczulski; Hanna Fojcik; Ewa Zukowska-Szczechowska; Ilona Szydlowska; Wladyslaw Grzeszczak

2003-01-01

310

Mice deficient in methylenetetrahydrofolate reductase exhibit tissue-specific distribution of folates.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate (5-methylTHF), which is used for homocysteine remethylation to methionine, the precursor of S-adenosylmethionine (SAM). Impairment of MTHFR will increase homocysteine levels and compromise SAM-dependent methylation reactions. Mild MTHFR deficiency is common in many populations due to a polymorphism at bp 677. To assess how impaired MTHFR activity affects folate metabolism in various tissues in vivo, we used affinity/HPLC with electrochemical detection to analyze the distribution of folates in plasma, liver, and brain of Mthfr-deficient mice. The most pronounced difference in total folate was observed in plasma. In Mthfr -/- mice, plasma total folate levels were approximately 25% of those in wild-type (Mthfr +/+) mice. Only 40% of plasma folate in Mthfr -/- mice was comprised of 5-methylTHF, compared with at least 80% in the other 2 genotype groups. In liver and brain, there were no differences in total folate. However, the proportion of 5-methylTHF in both tissues was again markedly reduced in mice with the Mthfr -/- genotype. In this genotype group, 5-methylTHF is likely derived from the diet. Our study demonstrated reduced total circulatory folate and altered distribution of folate derivatives in liver and brain in Mthfr deficiency. Decreased methylfolates and increased nonmethylfolates would affect the flux of one-carbon units between methylation reactions and nucleotide synthesis. This altered flux has implications for several common disorders, including cancer and vascular disease. PMID:15514261

Ghandour, Haifa; Chen, Zhoutao; Selhub, Jacob; Rozen, Rima

2004-11-01

311

Association of Polymorphisms in BDNF, MTHFR, and Genes Involved in the Dopaminergic Pathway with Memory in a Healthy Chinese Population  

ERIC Educational Resources Information Center

|The contribution of genetic factors to the memory is widely acknowledged. Research suggests that these factors include genes involved in the dopaminergic pathway, as well as the genes for brain-derived neurotrophic factor (BDNF) and methylenetetrahydrofolate reductase (MTHFR). The activity of the products of these genes is affected by single…

Yeh, Ting-Kuang; Hu, Chung-Yi; Yeh, Ting-Chi; Lin, Pei-Jung; Wu, Chung-Hsin; Lee, Po-Lei; Chang, Chun-Yen

2012-01-01

312

Influence of the MTHFR genotype on the rate of malformations following exposure to antiepileptic drugs in utero  

Microsoft Academic Search

Folate deficiency and the presence of the 677C>T (CT) polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene have been implicated in the causation of malformations in the fetus (particularly cleft lip and palate and neural tube defects). These birth defects are also recognised complications of exposure to antiepileptic drugs (AEDs). In pregnant women with epilepsy, the use of AEDs has an

Usha Kini; Rebecca Lee; Alison Jones; Sarah Smith; Simon Ramsden; Alan Fryer; Jill Clayton-Smith

2007-01-01

313

Prevalence of MTHFR C677T Polymorphism in North Indian Mothers Having Babies with Trisomy 21 Down Syndrome  

ERIC Educational Resources Information Center

|Recent studies have evaluated possible links between polymorphisms in maternal folate metabolism genes and Down syndrome. Some of these studies show a significantly increased prevalence of the C677T polymorphism of the 5,10-methylene tetrahydrofolate reductase (NADPH) gene (MTHFR) among mothers who have had babies with Down syndrome. This study…

Kohli, Utkarsh; Arora, Sadhna; Kabra, Madhulika; Ramakrishnan, Lakshmy; Gulati, Sheffali; Pandey, Ravindra

2008-01-01

314

Mefolinate (5-methyltetrahydrofolate), but not folic acid, decreases mortality in an animal model of severe methylenetetrahydrofolate reductase deficiency.  

PubMed

Severe deficiency of methylenetetrahydrofolate reductase (MTHFR) results in homocystinuria, with a variety of neurological and vascular complications, and sometimes death in the first year of life. MTHFR (EC 1.5.1.20) catalyses the synthesis of 5-methyltetrahydrofolate (5-methylTHF) which is required for homocysteine remethylation to methionine. Mthfr (-/-) mice are a good animal model of severe MTHFR deficiency in humans. They have marked hyperhomocysteinaemia and a high rate of mortality in the neonatal period. We attempted to rescue Mthfr (-/-) mice from postnatal death by treating their Mthfr (+/-) mothers with mefolinate (a synthetic form of 5-methylTHF, dissolved in their drinking water) or with a folic acid-enriched diet throughout pregnancy and lactation. We monitored pups' vitality and body weights until 3 weeks of age. The majority of Mthfr (-/-) pups from the control groups died during the first week of life. Body weights of -/- pups from control groups were significantly less than those of their Mthfr (+/-) and Mthfr ( +/+ ) littermates. Mefolinate treatment significantly improved survival rates (64% survival) in the -/- pups and improved morphology of the cerebellum. Folic acid supplementation did not affect the survival rate or body weights of the -/- pups. Our study suggests that MTHFR is important for postnatal growth and vitality, and that 5-methylTHF deficiency contributes to the high postnatal mortality. Mefolinate may be a good candidate drug for treatment of severe MTHFR deficiency. PMID:18415702

Li, D; Karp, N; Wu, Q; Wang, X-L; Melnyk, S; James, S J; Rozen, R

2008-04-14

315

MTHFR genetic polymorphism as a risk factor in Egyptian mothers with Down syndrome children.  

PubMed

Recent reports linking Down syndrome (DS) to maternal polymorphisms at the methylenetetrahydrofolate reductase (MTHFR) gene locus have generated great interest among investigators in the field. The present study aimed at evaluation of MTHFR 677C/T and 1298A/C polymorphisms in the MTHFR gene as maternal risk factors for DS. Forty two mothers of proven DS outcomes and forty eight control mothers with normal offspring were included. Complete medical and nutritional histories for all mothers were taken with special emphasis on folate intake. Folic acid intake from food or vitamin supplements was significantly low (below the Recommended Daily Allowance) in the group of case mothers compared to control mothers. Frequencies of MTHFR 677T and MTHFR 1298C alleles were significantly higher among case mothers (32.1% and 57.1%, respectively) compared to control mothers (18.7% and 32.3%, respectively). Heterozygous and homozygous genotype frequencies of MTHFR at position 677 (CT and TT) were higher among case mothers than controls (40.5% versus 25% and 11.9% versus 6.2%, respectively) with an odds ratio of 2.34 (95% confidence interval [CI] 0.93-5.89) and 2.75 (95% CI 0.95-12.77), respectively. Interestingly, the homozygous genotype frequency (CC) at position 1298 was significantly higher in case mothers than in controls (33.3% versus 2.1% respectively) with an odds ratio of 31.5 (95% CI 3.51 to 282.33) indicating that this polymorphism may have more genetic impact than 677 polymorphism. Heterozygous genotype (AC) did not show significant difference between the two groups. We here report on the first pilot study of the possible genetic association between DS and MTHFR 1298A/C genotypes among Egyptians. Further extended studies are recommended to confirm the present work. PMID:18057532

Meguid, Nagwa A; Dardir, Ahmed A; Khass, Mohamed; Hossieny, Lamia El; Ezzat, Afaf; El Awady, Mostafa K

2008-01-01

316

A literature review of MTHFR (C677T and A1298C polymorphisms) and cancer risk.  

PubMed

5,10-Methlenetetrahydrofolate reductase (MTHFR) is one of the most important enzymes for folate metabolism. This enzyme is mapped on chromosome 1, which is located at the end of the short arm (1p36.3). The C677T and A1298C are MTHFR polymorphisms that decrease in vitro MTHFR enzyme activity. Folate metabolism plays a key role in cell metabolism. These reactions are associated with purine-pyrimidine synthesis: DNA, RNA, and protein methylation. Polymorphism is also a factor in biodiversity, and be affected by ethnic heritage and geographic locale. In the case of unknown outcomes, not only should all geographical regions be investigated to ascertain biodiversity, but all populations as well to fully understand the variations in the effect. PUBMED was searched from January 2006 to December 2011 to develop an investigatory pursuit strategy. MTHFR, cancer, C677T, A1298C, and polymorphisms were key words used to focus the search. The literature review included all published relevant cancer types and MTHFR polymorphisms for that 5 years period. All selected polymorphisms data for cancer types was listed in tables for easy access and retrieval. PMID:23076526

Izmirli, Muzeyyen

2012-10-19

317

MTHFR association with arteriosclerotic vascular disease?  

Microsoft Academic Search

Complex diseases are far more common than diseases that follow simple Mendelian patterns of inheritance. Difficulties are\\u000a experienced in the designing of experiments to dissect out the contribution of a single allele to a complex phenotype. We\\u000a review the literature regarding a point mutation in methylenetetrahydrofolate reductase, a candidate gene for susceptibility\\u000a to vascular diseases.

Olivia Fletcher; Anna M. Kessling

1998-01-01

318

Polymorphisms of methylenetetrahydrofolate reductase and methionine synthase genes and bladder cancer risk: a case–control study with meta-analysis  

Microsoft Academic Search

Folate deficiency due to the methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS) variants leads to carcinogenesis\\u000a by affecting DNA synthesis, repair, and methylation. We hypothesized that the MTHFR C677T, A1298C, and MS A2756G polymorphisms are associated with risk of bladder cancer. In a case–control study of 239 bladder cancer cases and\\u000a 250 cancer-free controls, we found that the MTHFR 677TT

Meilin Wang; Haixia Zhu; Guangbo Fu; Miaomiao Wang; Zhizhong Zhang; Qiang Lu; Shizhi Wang; Zhengdong Zhang

2009-01-01

319

Methylenetetrahydrofolate reductase polymorphisms and breast cancer risk: a meta-analysis from 41 studies with 16,480 cases and 22,388 controls  

Microsoft Academic Search

The association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and breast cancer risk has been widely\\u000a reported, but results were inconsistent and underpowered. To clarify the effects of MTHFR polymorphisms on the risk of breast\\u000a cancer, an updated meta-analysis of all available studies relating C677T and\\/or A1298C polymorphisms of MTHFR gene to the\\u000a risk of breast cancer was conducted. Eligible articles

Xiaowei Qi; Xiangyu Ma; Xinhua Yang; Linjun Fan; Yi Zhang; Fan Zhang; Li Chen; Yan Zhou; Jun Jiang

2010-01-01

320

MTHFR polymorphisms’ influence on outcome and toxicity in acute lymphoblastic leukemia patients  

Microsoft Academic Search

Recently the influence of polymorphisms of different genes involved in metabolism of chemoterapic agents have been studied especially in childhood acute lymphoblastic leukemia (ALL). We evaluated the influence of C677T and A1298C methylenetetrahydrofolate reductase (MTHFR) polymorphisms on time to relapse and survival and on methotrexate (MTX) toxicity in 82 ALL adult patients.Relapse free survival and event free survival between homozygous

Patrizia Chiusolo; Giovanni Reddiconto; Giuliana Farina; Alice Mannocci; Alessia Fiorini; Mariangela Palladino; Giuseppe La Torre; Luana Fianchi; Federica Sorŕ; Luca Laurenti; Giuseppe Leone; Simona Sica

2007-01-01

321

Polymorphisms in MTHFR, MS and CBS Genes and Homocysteine Levels in a Pakistani Population  

Microsoft Academic Search

BackgroundHyperhomocysteinemia (>15 µmol\\/L) is highly prevalent in South Asian populations including Pakistan. In order to investigate the genetic determinants of this condition, we studied 6 polymorphisms in genes of 3 enzymes - methylenetetrahydrofolate reductase (MTHFR; C677T; A1298C), methionine synthase (MS; A2756G), cystathionine-?-synthase (CBS; T833C\\/844ins68, G919A) involved in homocysteine metabolism and investigated their interactions with nutritional and environmental factors in a

Mohsin Yakub; Naushad Moti; Siddiqa Parveen; Bushra Chaudhry; Iqbal Azam; Mohammad Perwaiz Iqbal

2012-01-01

322

One-Carbon Metabolism, MTHFR Polymorphisms, and Risk of Breast Cancer  

Microsoft Academic Search

Accumulating evidence from epidemiologic studies suggests that risk of breast cancer is reduced in relation to increased consumption of folate and related B vitamins. We investigated independent and joint effects of B vitamin intake as well as two polymorphisms of a key one-carbon metabolizing gene (i.e., methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C) on breast cancer risk. The study uses the

Jia Chen; Marilie D. Gammon; Wendy Chan; Caroline Palomeque; James G. Wetmur; Geoffrey C. Kabat; Susan L. Teitelbaum; Julie A. Britton; Mary Beth Terry; Alfred I. Neugut; Regina M. Santella

2005-01-01

323

Molecular biology of 5,10-methylenetetrahydrofolate reductase.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the folate cycle and contributes to the metabolism of the amino acid homocysteine. It catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, thus generating the active form of folate required for remethylation of homocysteine to methionine. Deficiency of MTHFR may be associated with an increase in plasma homocysteine, which in turn is associated with an increased risk of vascular disease. This article summarizes the biochemistry, the function in the folate cycle, and the molecular genetics of this enzyme. Particular emphasis has been given to the role of two common polymorphisms (MTHFR 677C-->T, 1298A-->C) in cardiovascular disease, cerebrovascular disease, venous thrombosis, longevity, neural tube defects, pregnancy/preeclampsia, diabetes, cancer, psychiatry, renal failure and renal replacement therapy. Finally, the rare genetic defects underlying severe MTHFR deficiency are also considered. PMID:10720211

Födinger, M; Hörl, W H; Sunder-Plassmann, G

324

Thermolabile Methylenetetrahydrofolate Reductase C677T Polymorphism and Homocysteine Are Risk Factors for Coronary Artery Disease in Moroccan Population  

PubMed Central

Increased plasma total homocysteine (tHcy) levels have been shown to be a risk factor for coronary artery disease (CAD). The common methylenetetrahydrofolate reductase C677T (MTHFR C677T) polymorphism has been reported to be a strong predictor of mild hyperhomocysteinaemia (HHcy). We assessed whether this mutation was associated with increased risk of CAD and plasma levels of tHcy. We also evaluated interactions between this polymorphism, mild elevated tHcy levels and conventional risk factors of CAD. Method. Using PCR-RFLP analysis, we studied the frequency of the C677T genotypes and its effect on CAD and on tHcy concentrations in 400 subjects without and with CAD angiographically confirmed. There were 210 subjects with CAD and 190 subjects without CAD. Results. The frequencies of the C677T genotypes were 53% (59.5% in controls versus 48.1% in cases), 34.8% (32.1 in controls versus 37.1 in cases), and 11.8% (8.4% in controls versus 14.8% in cases), respectively, for 677CC, 677CT, and 677TT. The genotype frequencies were significantly different between case and control groups (P < .05). The 677T allele enhances the risk of CAD associated to HHcy (P < .01). In multivariate analysis models, MTHFR C677T polymorphism effect on CAD was masked by other risk factors. HHcy was only and independently influenced by MTHFR polymorphism and smoking habits, and it is a strong predictor of CAD independently of conventional risk factors. Conclusion. Our data suggest that HHcy is strongly and independently associated to CAD risk increase; and MTHFR C677T polymorphism and smoking habits were the main predictors of tHcy levels. The CAD risk increase is mainly associated with mild HHcy in 677TT, whereas in 677CT and 677CC it is mainly associated with the conventional risk factors.

Bennouar, Nawal; Allami, Abdellatif; Azeddoug, Houssine; Bendris, Abdenbi; Laraqui, Abdelilah; El Jaffali, Amal; El Kadiri, Nizar; Benzidia, Rachid; Benomar, Anwar; Fellat, Seddik; Benomar, Mohamed

2007-01-01

325

Clinical, fluorine-18 labeled 2-fluoro-2-deoxyglucose positron emission tomography of the brain, MR spectroscopy, and therapeutic attempts in methylenetetrahydrofolate reductase deficiency  

Microsoft Academic Search

The cases of three infants, two Saudi and one Bahraini, with methylenetetrahydrofolate reductase (MTHFR) deficiency are reported. They presented in the neonatal period with lethargy, poor feeding, hypotonia, and frequent apneas. Tandem mass spectrometry (MS\\/MS) of a blood spot indicated very low methionine level and of urine revealed high homocysteine. The diagnosis was confirmed by demonstrating severe deficiency of MTHFR

M. A. Al-Essa; A. Al Amir; M. Rashed; E. Al Jishi; A. Abutaleb; K. Mobaireek; Y. S. Shin; P. T. Ozand

1999-01-01

326

Multiplex PCR for simultaneous detection of 677 C?T and 1298 A?C polymorphisms in methylenetetrahydrofolate reductase gene for population studies of cancer risk  

Microsoft Academic Search

Methylenetetrahydrofolate reductase (MTHFR) plays a pivotal role in folate metabolism by regulating the diversion of folate metabolites toward DNA methylation or toward DNA synthesis. Because aberrations in both of these pathways can be tumor promoting, the two common polymorphisms in the MTHFR gene, 677 C?T and 1298 A?C, have been implicated as risk factors for several cancers. Homozygosity for the

Ping Yi; Igor P. Pogribny; S. Jill James

2002-01-01

327

LINKAGE DISEQUILIBRIUM BETWEEN THE 677C>T AND 1298A>C POLYMORPHISMS IN HUMAN METHYLENETETRAHYDROFOLATE REDUCTASE GENE AND THEIR CONTRIBUTIONS TO RISK OF COLORECTAL CANCER  

Technology Transfer Automated Retrieval System (TEKTRAN)

A common polymorphism in a folate-metabolizing gene, methylenetetrahydrofolate reductase (MTHFR) 677C>T has been associated with reduced risk of colorectal cancer. In this study, we investigated whether a second common polymorphism of the gene, MTHFR 1298A>C, is an independent risk factor for colore...

328

Association of methylenetetrahydrofolate reductase C677T polymorphism and serum lipid levels in the Guangxi Bai Ku Yao and Han populations  

Microsoft Academic Search

BACKGROUND: The association of methylenetetrahydrofolate reductase (MTHFR) gene polymorphism and serum lipid profiles is still controversial in diverse ethnics. Bai Ku Yao is an isolated subgroup of the Yao minority in China. The aim of the present study was to eveluate the association of MTHFR C677T polymorphism and several environmental factors with serum lipid levels in the Guangxi Bai Ku

Lin Zhang; Rui-Xing Yin; Wan-Ying Liu; Lin Miao; Dong-Feng Wu; Lynn Htet Htet Aung; Xi-Jiang Hu; Xiao-Li Cao; Jin-Zhen Wu; Shang-Ling Pan

2010-01-01

329

Roles for menaquinone and the two trimethylamine oxide (TMAO) reductases in TMAO respiration in Salmonella typhimurium: Mu d(Apr lac) insertion mutations in men and tor.  

PubMed

Three groups of mutants defective in trimethylamine oxide (TMAO) reduction were isolated from Salmonella typhimurium LT2 subjected to transposition mutagenesis with Mu d(Apr lac). Mutants were identified by their acidic reaction on a modified MacConkey-TMAO medium. Group I consisted of pleiotropic chlorate-resistant mutants which were devoid of TMAO reductase activity. None expressed the lac operon. Group II mutants were partially defective in TMAO reductase. Electrophoretic studies revealed that they lacked the inducible TMAO reductase, but retained the constitutive activity. The genotypic designation tor was suggested for these mutants. The tor mutation in one was located between 80 and 83 U on the S. typhimurium chromosome. Expression of the lac operon in these mutants was not affected by air, TMAO, or nitrate. Group III mutants reduced little or no TMAO in vivo, but their extracts retained full capacity to reduce it with methyl viologen. These mutants also failed to produce hydrogen sulfide from thiosulfate and could not grow anaerobically on glycerol-fumarate. Two subgroups were distinguished. Vitamin K5 restored wild-type phenotype in subgroup IIIa only; vitamin K1 restored wild-type phenotype in both IIIa and IIIb isolates. The genotypic designation men (menaquinone) was suggested for group III isolates. The mutation in IIIa mutants was cotransducible with glpT, which corresponds to the menBCD site in Escherichia coli. That in IIIb mutants was cotransducible with glpK, which corresponds to the menA site in E. coli. Expression of the lac operon in IIIa, but not IIIb, mutants was repressed by air. An additional mutant group isolated on the same medium consisted of strains defective in formate hydrogenlyase. PMID:6309742

Kwan, H S; Barrett, E L

1983-09-01

330

Symptomatic and asymptomatic methylenetetrahydrofolate reductase deficiency in two adult brothers.  

PubMed

We describe two brothers with 5,10-methylene tetrahydrofolate reductase (MTHFR) deficiency. The younger patient first developed limb weakness, incoordination, paresthesiae, and memory lapses at age 15 years, and by his early twenties he was wheelchair bound. His older brother remains asymptomatic at age 37 years. Both had homocystinuria and homocystinemia and low plasma levels of methionine. MTHFR activities in cultured skin fibroblasts of both patients were < 10% control and residual enzyme activities were markedly reduced on heating. The parents had intermediate enzyme activities and the reductase in the father (who had unexplained paraparesis and homocystinemia), but not in the mother, was also thermolabile. Both patients were treated with oral folate and betaine which improved, but did not totally correct, their biochemical abnormality. MTHFR deficiency should be considered in the differential diagnosis of unexplained neurologic disease in adolescents and adults. PMID:8456826

Haworth, J C; Dilling, L A; Surtees, R A; Seargeant, L E; Lue-Shing, H; Cooper, B A; Rosenblatt, D S

1993-03-01

331

Mthfr deficiency induces endothelial progenitor cell senescence via uncoupling of eNOS and downregulation of SIRT1.  

PubMed

Hyperhomocysteinemia (HHcy) has been shown to induce endothelial dysfunction in part as a result of enhanced oxidative stress. Function and survival of endothelial progenitor cells (EPCs, defined as sca1(+) c-kit(+) flk-1(+) bone marrow-derived cells), which significantly contribute to neovascularization and endothelial regeneration, depend on controlled production of reactive oxygen species (ROS). Mice heterozygous for the gene deletion of methylenetetrahydrofolate reductase (Mthfr(+/-)) have a 1.5- to 2-fold elevation in plasma homocysteine. This mild HHcy significantly reduced the number of circulating EPCs as well as their differentiation. Mthfr deficiency was also associated with increased ROS production and reduced nitric oxide (NO) generation in Mthfr(+/-) EPCs. Treatment of EPCs with sepiapterin, a precursor of tetrahydrobiopterin (BH(4)), a cofactor of endothelial nitric oxide synthase (eNOS), significantly reduced ROS and improved NO production. mRNA and protein expression of eNOS and the relative amount of eNOS dimer compared with monomer were decreased by Mthfr deficiency. Impaired differentiation of EPCs induced by Mthfr deficiency correlated with increased senescence, decreased telomere length, and reduced expression of SIRT1. Addition of sepiapterin maintained cell senescence and SIRT1 expression at levels comparable to the wild type. Taken together, these results demonstrate that Mthfr deficiency impairs EPC formation and increases EPC senescence by eNOS uncoupling and downregulation of SIRT1. PMID:21169404

Lemarié, Catherine A; Shbat, Layla; Marchesi, Chiara; Angulo, Orlando J; Deschęnes, Marie-Eve; Blostein, Mark D; Paradis, Pierre; Schiffrin, Ernesto L

2010-12-17

332

A systematic review and meta-analysis of MTHFR polymorphisms in methotrexate toxicity prediction in pediatric acute lymphoblastic leukemia.  

PubMed

Methotrexate (MTX) is an important component of therapy used to treat childhood acute lymphoblastic leukemia (ALL). Two single-nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene, C677T and A1298C, affect MTHFR activity. A large body of studies has investigated the potential role of MTHFR SNPs in MTX toxicity in pediatric ALL. However, the results are controversial. In this review and meta-analysis, we critically evaluate the relationship between the C677T and A1298C polymorphisms of MTHFR and MTX toxicity in pediatric ALL. The majority of published reports do not find associations between MTHFR polymorphisms and toxicity in pediatric ALL. When associations are reported, often the results are contradictory to each other. The meta-analysis confirms a lack of association. In conclusion, MTHFR, C677T and A1298C polymorphisms do not seem to be good markers of MTX-related toxicity in pediatric ALL.The Pharmacogenomics Journal advance online publication, 23 October 2012; doi:10.1038/tpj.2012.44. PMID:23089671

Lopez-Lopez, E; Martin-Guerrero, I; Ballesteros, J; Garcia-Orad, A

2012-10-23

333

MTHFR 677CC/1298CC genotypes are highly associated with chronic myelogenous leukemia: a case-control study in Korea.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in folate metabolism and DNA methylation. Studies on MTHFR polymorphism in leukemia have largely focused on the protective role of MTHFR polymorphism in acute lymphoblastic leukemia (ALL). We evaluated the C677T and A1298C polymorphisms using the TaqMan allelic discrimination assay in various malignancies. The study population included 115 subjects with chronic myelogenous leukemia (CML), 200 with acute myelogenous leukemia (AML), 196 with multiple myeloma (MM) and 434 healthy control subjects. The frequency of 1298CC was statistically significantly higher in subjects with CML than that of the controls (OR=5.12, 95% CI: 1.75-14.9, P-value=.003). Of note, the frequencies of 677CC/1298CC genotype were statistically significantly higher in subjects with CML, AML and MM than that of the controls (OR=8.8, 3.5, 3.83, P-value=.002, 0.036, 0.023, respectively). Our results demonstrate that the MTHFR 1298CC homozygote variant is strongly associated with an increased risk of CML, while MTHFR C677T does not significantly affect the risk of CML. Moreover, we demonstrated that MTHFR 677CC and 1298CC genotype might have combined effect on risk of CML, AML and MM and it is inferred that the A1298C may play a different role in carcinogenesis, depending on the types of organs involved, the types of disease entities and the genotype of C677T. PMID:17156840

Moon, Hee Won; Kim, Tae Young; Oh, Bo Ra; Min, Hyun Chung; Cho, Han Ik; Bang, Soo Mee; Lee, Jae Hoon; Yoon, Sung Soo; Lee, Dong Soon

2006-12-06

334

Methylenetetrahydrofolate reductase gene polymorphisms in Turkish children with attention-deficit/hyperactivity disorder.  

PubMed

Attention-deficit/hyperactivity disorder (ADHD) is a common, multifactorial genetic disorder. The aim of the present study was to evaluate a possible association between 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and ADHD. There is evidence to suggest that MTHFR C677T and A1298C polymorphisms alter the function of the enzyme, causing reduced folate and increased homocysteine levels in plasma. Two polymorphisms of the MTHFR gene, C677T (rs1801133) and A1298C (rs1801131), were analyzed in a sample of 100 Diagnostic and Statistical Manual of Mental Disorders-IV-diagnosed ADHD and 300 healthy controls using a polymerase chain reaction-restriction fragment length polymorphism method. We did not find any association between MTHFR 677T allele, MTHFR 1298C allele, and ADHD. In addition, there was no genotype association between the MTHFR gene and ADHD (?(2)=1.711; df=2; p=0.425; ?(2)=2.946; df=2; p=0.229). Our data suggest that neither the MTHFR C677T polymorphism nor the MTHFR A1298C polymorphism was associated with ADHD in Turkish children. Thus, the MTHFR gene does not seem to play a role in the etiopathogenesis of ADHD in the cohort studied. PMID:21819229

Ergul, Emel; Sazci, Ali; Kara, Ihsan

2011-08-05

335

ALLELIC ASSOCIATION OF THE METHYLENETETRAHYDROFOLATE REDUCTASE GENE WITH SCHIZOPHRENIA  

Microsoft Academic Search

SUMMARY The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene is located at the end of the short arm of chromosome 1 and contains 11 exons. A single nucleotide polymorphism has been reported in the fifth exon at the nucleotide 677 where occurs a transition CT. This causes the replacement of alanin with valine in the 222 position of the protein. The consequences of

Anet Monica Chilici; Beatrix-Katalin Ferencz; O. Popescu

336

Methylenetetrahydrofolate reductase genotype association with the risk of follicular lymphoma  

Microsoft Academic Search

The metabolism of folate is essential in DNA synthesis, and polymorphisms of genes involved in such metabolism have been implicated in many types of cancer. Among these, the methylene tetrahydrofolate reductase gene (MTHFR) encodes an enzyme that converts folate to a methyl donor used for DNA methylation. We studied the association between the different genotypes of the two most common

Said I. Ismail; Nida A. Ababneh; Yousef Khader; Ahmad A. Abu-Khader; Abdullah Awidi

2009-01-01

337

Methotrexate-induced apoptosis is enhanced by altered expression of methylenetetrahydrofolate reductase.  

PubMed

Folates are essential for DNA synthesis and methylation reactions. The antifolate methotrexate (MTX) is a widely used chemotherapeutic drug which inhibits DNA synthesis and induces apoptosis. Changes in activity of a critical folate-metabolizing enzyme, methylenetetrahydrofolate reductase (MTHFR), might alter the chemosensitivity to MTX, as the MTHFR substrate is required for nucleotide synthesis and its product is used in homocysteine remethylation to methionine. Mild MTHFR deficiency is common in many populations due to a polymorphism at bp 677. We previously showed that altered expression of MTHFR enhanced MTX-induced myelosuppression in mice. To determine the cause of the impaired hematopoietic profile in mice with decreased or increased MTHFR expression, we evaluated MTX-induced apoptosis in the major hemolytic organ, spleen, using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) staining and caspase-3/7 activity assays, in MTHFR-deficient mice and in MTHFR-overexpressing mice after MTX administration. Decreased or increased expression of MTHFR in mice significantly increased TUNEL-positive cells and caspase-3/7 activities in MTX-treated spleen, compared with that of wild-type littermates. Plasma homocysteine levels correlated with apoptotic index in MTX-treated MTHFR-deficient mice and dUTP/dTTP ratios correlated with apoptotic index in MTX-treated MTHFR-overexpressing mice. The increased apoptosis may therefore relate to hyperhomocysteinemia and deoxyribonucleotide pool imbalances, respectively. Our results suggest that MTHFR underexpression and overexpression enhances MTX-induced apoptosis and myelosuppression, and that genotyping for the MTHFR polymorphism may have therapeutic implications. PMID:19593106

Celtikci, Basak; Lawrance, Andrea K; Wu, Qing; Rozen, Rima

2009-10-01

338

Gender-Specific Effect of Mthfr Genotype and Neonatal Vigabatrin Interaction on Synaptic Proteins in Mouse Cortex  

PubMed Central

The enzyme methylenetetrahydrofolate reductase (MTHFR) is a part of the homocysteine and folate metabolic pathways, affecting the methylations of DNA, RNA, and proteins. Mthfr deficiency was reported as a risk factor for neurodevelopmental disorders such as autism spectrum disorder and schizophrenia. Neonatal disruption of the GABAergic system is also associated with behavioral outcomes. The interaction between the epigenetic influence of Mthfr deficiency and neonatal exposure to the GABA potentiating drug vigabatrin (GVG) in mice has been shown to have gender-dependent effects on mice anxiety and to have memory impairment effects in a gender-independent manner. Here we show that Mthfr deficiency interacts with neonatal GABA potentiation to alter social behavior in female, but not male, mice. This impairment was associated with a gender-dependent enhancement of proteins implicated in excitatory synapse plasticity in the female cortex. Reelin and fragile X mental retardation 1 protein (FMRP) levels and membrane GluR1/GluR2 ratios were elevated in wild-type mice treated neonatally with GVG and in Mthfr+/? mice treated with saline, but not in Mthfr+/? mice treated with GVG, compared with control groups (wild type treated with saline). A minor influence on the levels of these proteins was observed in male mice cortices, possibly due to high basal protein levels. Interaction between gender, genotype, and treatment was also observed in the GABA pathway. In female mice, GABA A?2/gephyrin ratios were suppressed in all test groups; in male mice, a genotype-specific enhancement of GABA A?2/gephyrin was observed. The lack of an effect on either reln or Fmr1 transcription suggests post-transcriptional regulation of these genes. Taken together, these findings suggest that Mthfr deficiency may interact with neonatal GABA potentiation in a gender-dependent manner to interrupt synaptic function. This may illustrate a possible mechanism for the epigenetic involvement of Mthfr deficiency in neurodevelopmental disorders.

Blumkin, Elinor; Levav-Rabkin, Tamar; Melamed, Osnat; Galron, Dalia; Golan, Hava M

2011-01-01

339

Gender-specific effect of Mthfr genotype and neonatal vigabatrin interaction on synaptic proteins in mouse cortex.  

PubMed

The enzyme methylenetetrahydrofolate reductase (MTHFR) is a part of the homocysteine and folate metabolic pathways, affecting the methylations of DNA, RNA, and proteins. Mthfr deficiency was reported as a risk factor for neurodevelopmental disorders such as autism spectrum disorder and schizophrenia. Neonatal disruption of the GABAergic system is also associated with behavioral outcomes. The interaction between the epigenetic influence of Mthfr deficiency and neonatal exposure to the GABA potentiating drug vigabatrin (GVG) in mice has been shown to have gender-dependent effects on mice anxiety and to have memory impairment effects in a gender-independent manner. Here we show that Mthfr deficiency interacts with neonatal GABA potentiation to alter social behavior in female, but not male, mice. This impairment was associated with a gender-dependent enhancement of proteins implicated in excitatory synapse plasticity in the female cortex. Reelin and fragile X mental retardation 1 protein (FMRP) levels and membrane GluR1/GluR2 ratios were elevated in wild-type mice treated neonatally with GVG and in Mthfr+/- mice treated with saline, but not in Mthfr+/- mice treated with GVG, compared with control groups (wild type treated with saline). A minor influence on the levels of these proteins was observed in male mice cortices, possibly due to high basal protein levels. Interaction between gender, genotype, and treatment was also observed in the GABA pathway. In female mice, GABA A?2/gephyrin ratios were suppressed in all test groups; in male mice, a genotype-specific enhancement of GABA A?2/gephyrin was observed. The lack of an effect on either reln or Fmr1 transcription suggests post-transcriptional regulation of these genes. Taken together, these findings suggest that Mthfr deficiency may interact with neonatal GABA potentiation in a gender-dependent manner to interrupt synaptic function. This may illustrate a possible mechanism for the epigenetic involvement of Mthfr deficiency in neurodevelopmental disorders. PMID:21490592

Blumkin, Elinor; Levav-Rabkin, Tamar; Melamed, Osnat; Galron, Dalia; Golan, Hava M

2011-04-13

340

Maternal MTHFR genotype and haplotype predict deficits in early cognitive development in a lead-exposed birth cohort in Mexico City1234  

PubMed Central

Background: Maternal folate nutritional status and prenatal lead exposure can influence fetal development and subsequent health. The methylenetetrahydrofolate reductase (MTHFR) gene is important for folate metabolism, and 2 common polymorphisms, C677T and A1298C, reduce enzymatic activity; C677T is present at high penetrance in Mexican populations. Objective: The objective of this study was to examine potential links between maternal and child MTHFR polymorphisms and child neurodevelopment in a lead-exposed population. Design: Data regarding MTHFR polymorphisms C677T and A1298C, peri- and postnatal lead measures, and Bayley Mental Development Index at 24 mo of age (MDI-24) scores were available for 255 mother-child pairs who participated in the ELEMENT (Early Life Exposures in Mexico to Environmental Toxicants) study during 1994–1995. Results: In covariate-adjusted regression models, maternal MTHFR 677 genotype predicted MDI-24 scores, in which each copy of the maternal MTHFR 677T variant allele was associated with lower MDI-24 scores (? = ?3.52; 95% CI: ?6.12, ?0.93; P = 0.004). Maternal MTHFR haplotype also predicted MDI-24 scores (mean ± SE: 93.3 ± 1.2 for 677C-1298A compared with 89.9 ± 0.8 for 677T-1298A; P < 0.05). MDI-24 scores were not associated with maternal MTHFR 1298 genotype or child MTHFR genotypes. We did not observe significant MTHFR genotype × lead interactions with respect to any of the subject biomarkers of lead exposure. Conclusions: The maternal MTHFR 677T allele is an independent predictor of poorer child neurodevelopment at 24 mo. These results suggest that maternal genetic variations in folate metabolism during pregnancy may program offspring neurodevelopment trajectories. Further research is warranted to determine the generalizability of these results across other populations.

Hu, Howard; Wright, Robert O; Kordas, Katarzyna; Ettinger, Adrienne S; Sanchez, Brisa N; Cantonwine, David; Lazarus, Alicia L; Cantoral, Alejandra; Schnaas, Lourdes; Tellez-Rojo, Martha Maria; Hernandez-Avila, Mauricio

2010-01-01

341

Hydrocephalus internus in two patients with 5,10-methylenetetrahydrofolate reductase deficiency.  

PubMed

Hydrocephalus internus (HCI) of all four ventricles in association with early neurological abnormalities is described as the presenting symptom in two patients with 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency. Decreased activity of MTHFR leads to reduction of 5-methyltetrahydrofolate, the main methyl donor for methionine synthesis necessary for synthesis of S-adenosyl-methionine (SAM). Demyelination in MTHFR deficiency has been attributed to low SAM levels in the brain. The biochemical hallmarks of the disorder are hyperhomocystinemia, homocystinuria and low levels of plasma methionine. Hydrocephalus internus requiring neurosurgical intervention has to our knowledge not been reported as a presenting feature of homocystinuria due to deficiency of MTHFR so far. The surprising finding of HCI of all four ventricles in MTHFR deficiency must be kept in mind when evaluating patients with hydrocephalus of unknown origin. PMID:11508552

Baethmann, M; Wendel, U; Hoffmann, G F; Göhlich-Ratmann, G; Kleinlein, B; Seiffert, P; Blom, H; Voit, T

2000-12-01

342

In Vitro Activity of Antifolate and Polymorphism in Dihydrofolate Reductase of Plasmodium falciparum Isolates from the Kenyan Coast: Emergence of Parasites with Ile-164-Leu Mutation?  

PubMed Central

We have analyzed the activities of the antifolates pyrimethamine (PM), chlorcycloguanil (CCG), WR99210, trimethoprim (TMP), methotrexate (MTX), and trimetrexate (TMX) against Kenyan Plasmodium falciparum isolates adapted in vitro for long-term culture. We have also assessed the relationship between these drug activities and mutations in dihydrofolate reductase (dhfr), a domain of the gene associated with antifolate resistance. As expected, WR99210 was the most potent drug, with a median 50% inhibitory concentration (IC50) of <0.075 nM, followed by TMX, with a median IC50 of 30 nM. The median IC50 of CCG was 37.80 nM, and that of MTX was 83.60 nM. PM and TMP were the least active drugs, with median IC50s of 733.26 nM and 29,656.04 nM, respectively. We analyzed parasite dhfr genotypes by the PCR-enzyme restriction technique. No wild-type dhfr parasite was found. Twenty-four of 33 parasites were triple mutants (mutations at codons 108, 51, and 59), and only 8/33 were double mutants (mutations at codons 108 and 51 or at codons 108 and 59). IC50s were 2.1-fold (PM) and 3.6-fold (TMP) higher in triple than in double mutants, though these differences were not statistically significant. Interestingly, we have identified a parasite harboring a mutation at codon 164 (Ile-164-Leu) in addition to mutations at codons 108, 51, and 59. This quadruple mutant parasite had the highest TMP IC50 and was in the upper 10th percentile against PM and CCG. We confirmed the presence of this mutation by sequencing. Thus, TMX and MTX are potent against P. falciparum, and quadruple mutants are now emerging in Africa.

Kiara, Steven M.; Okombo, John; Masseno, Victor; Mwai, Leah; Ochola, Isabella; Borrmann, Steffen; Nzila, Alexis

2009-01-01

343

In vitro activity of antifolate and polymorphism in dihydrofolate reductase of Plasmodium falciparum isolates from the Kenyan coast: emergence of parasites with Ile-164-Leu mutation.  

PubMed

We have analyzed the activities of the antifolates pyrimethamine (PM), chlorcycloguanil (CCG), WR99210, trimethoprim (TMP), methotrexate (MTX), and trimetrexate (TMX) against Kenyan Plasmodium falciparum isolates adapted in vitro for long-term culture. We have also assessed the relationship between these drug activities and mutations in dihydrofolate reductase (dhfr), a domain of the gene associated with antifolate resistance. As expected, WR99210 was the most potent drug, with a median 50% inhibitory concentration (IC50) of <0.075 nM, followed by TMX, with a median IC50 of 30 nM. The median IC50 of CCG was 37.80 nM, and that of MTX was 83.60 nM. PM and TMP were the least active drugs, with median IC50s of 733.26 nM and 29,656.04 nM, respectively. We analyzed parasite dhfr genotypes by the PCR-enzyme restriction technique. No wild-type dhfr parasite was found. Twenty-four of 33 parasites were triple mutants (mutations at codons 108, 51, and 59), and only 8/33 were double mutants (mutations at codons 108 and 51 or at codons 108 and 59). IC50s were 2.1-fold (PM) and 3.6-fold (TMP) higher in triple than in double mutants, though these differences were not statistically significant. Interestingly, we have identified a parasite harboring a mutation at codon 164 (Ile-164-Leu) in addition to mutations at codons 108, 51, and 59. This quadruple mutant parasite had the highest TMP IC50 and was in the upper 10th percentile against PM and CCG. We confirmed the presence of this mutation by sequencing. Thus, TMX and MTX are potent against P. falciparum, and quadruple mutants are now emerging in Africa. PMID:19528269

Kiara, Steven M; Okombo, John; Masseno, Victor; Mwai, Leah; Ochola, Isabella; Borrmann, Steffen; Nzila, Alexis

2009-06-15

344

Defining the role of mutations in Plasmodium vivax dihydrofolate reductase-thymidylate synthase gene using an episomal Plasmodium falciparum transfection system.  

PubMed

Plasmodium vivax resistance to antifolates is prevalent throughout Australasia and is caused by point mutations within the parasite dihydrofolate reductase (DHFR)-thymidylate synthase. Several unique mutations have been reported in P. vivax DHFR, and their roles in resistance to classic and novel antifolates are not entirely clear due, in part, to the inability to culture P. vivax in vitro. In this study, we use a homologous system to episomally express both wild-type and various mutant P. vivax dhfr (pvdhfr) alleles in an antifolate-sensitive line of P. falciparum and to assess their influences on the susceptibility of the recipient P. falciparum line to commonly used and new antifolate drugs. Although the wild-type pvdhfr-transfected P. falciparum line was as susceptible to antifolate drugs as the P. falciparum parent line, the single (117N), double (57L/117T and 58R/117T), and quadruple (57L/58R/61M/117T) mutant pvdhfr alleles conferred a marked reduction in their susceptibilities to antifolates. The resistance index increased with the number of mutations in these alleles, indicating that these mutations contribute to antifolate resistance directly. In contrast, the triple mutant allele (58R/61M/117T) significantly reversed the resistance to all antifolates, indicating that 61M may be a compensatory mutation. These findings help elucidate the mechanism of antifolate resistance and the effect of existing mutations in the parasite population on the current and new generation of antifolate drugs. It also demonstrates that the episomal transfection system has the potential to provide a rapid screening system for drug development and for studying drug resistance mechanisms in P. vivax. PMID:20566761

Auliff, Alyson M; Adams, John H; O'Neil, Michael T; Cheng, Qin

2010-06-21

345

Defining the Role of Mutations in Plasmodium vivax Dihydrofolate Reductase-Thymidylate Synthase Gene Using an Episomal Plasmodium falciparum Transfection System?  

PubMed Central

Plasmodium vivax resistance to antifolates is prevalent throughout Australasia and is caused by point mutations within the parasite dihydrofolate reductase (DHFR)-thymidylate synthase. Several unique mutations have been reported in P. vivax DHFR, and their roles in resistance to classic and novel antifolates are not entirely clear due, in part, to the inability to culture P. vivax in vitro. In this study, we use a homologous system to episomally express both wild-type and various mutant P. vivax dhfr (pvdhfr) alleles in an antifolate-sensitive line of P. falciparum and to assess their influences on the susceptibility of the recipient P. falciparum line to commonly used and new antifolate drugs. Although the wild-type pvdhfr-transfected P. falciparum line was as susceptible to antifolate drugs as the P. falciparum parent line, the single (117N), double (57L/117T and 58R/117T), and quadruple (57L/58R/61M/117T) mutant pvdhfr alleles conferred a marked reduction in their susceptibilities to antifolates. The resistance index increased with the number of mutations in these alleles, indicating that these mutations contribute to antifolate resistance directly. In contrast, the triple mutant allele (58R/61M/117T) significantly reversed the resistance to all antifolates, indicating that 61M may be a compensatory mutation. These findings help elucidate the mechanism of antifolate resistance and the effect of existing mutations in the parasite population on the current and new generation of antifolate drugs. It also demonstrates that the episomal transfection system has the potential to provide a rapid screening system for drug development and for studying drug resistance mechanisms in P. vivax.

Auliff, Alyson M.; Adams, John H.; O'Neil, Michael T.; Cheng, Qin

2010-01-01

346

Interaction between the MTHFR C677T polymorphism and traumatic childhood events predicts depression  

PubMed Central

Childhood trauma is associated with the onset and recurrence of major depressive disorder (MDD). The thermolabile T variant of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism (rs1801133) is associated with a limited (oxidative) stress defense. Therefore, C677T MTHFR could be a potential predictor for depressive symptomatology and MDD recurrence in the context of traumatic stress during early life. We investigated the interaction between the C677T MTHFR variant and exposure to traumatic childhood events (TCEs) on MDD recurrence during a 5.5-year follow-up in a discovery sample of 124 patients with recurrent MDD and, in an independent replication sample, on depressive symptomatology in 665 healthy individuals from the general population. In the discovery sample, Cox regression analysis revealed a significant interaction between MTHFR genotype and TCEs on MDD recurrence (P=0.017). Over the 5.5-year follow-up period, median time to recurrence was 191 days for T-allele carrying patients who experienced TCEs (T+ and TCE+); 461 days for T? and TCE+ patients; 773 days for T+ and TCE? patients and 866 days for T? and TCE? patients. In the replication sample, a significant interaction was present between the MTHFR genotype and TCEs on depressive symptomatology (P=0.002). Our results show that the effects of TCEs on the prospectively assessed recurrence of MDD and self-reported depressive symptoms in the general population depend on the MTHFR genotype. In conclusion, T-allele carriers may be at an increased risk for depressive symptoms or MDD recurrence after exposure to childhood trauma.

Lok, A; Bockting, C L H; Koeter, M W J; Snieder, H; Assies, J; Mocking, R J T; Vinkers, C H; Kahn, R S; Boks, M P; Schene, A H

2013-01-01

347

Deep Sequencing Study of the MTHFR Gene to Identify Variants Associated with Myelomeningocele  

PubMed Central

INTRODUCTION Neural tube defects (NTDs) are congenital anomalies caused by a combination of genetic and environmental influences. A defect below the head region resulting in protuberance of meninges and nervous tissue is termed myelomeningocele (MM). MM, the most common NTD compatible with survival, occurs in approximately 1 in 1,000 births worldwide. Maternal pre- and periconceptional folate supplementation reduces the risk of NTDs by up to 70%. A key enzyme in folate metabolism is 5, 10-methylene-tetrahydrofolate reductase (MTHFR). OBJECTIVES Sequence the 12 exons of the MTHFR gene among 96 subjects with MM to identify variants potentially contributing to the disease trait. METHODS Exons were amplified by polymerase chain reaction and the products were sequenced by Sanger method to reveal sequence variants compared to MTHFR reference sequences. Association of variants was examined by Fisher’s test. RESULTS A novel variant c.171+3G>T was identified in intron 1 in one affected subject. The variant was not found in the subject’s unaffected mother’s DNA and the unaffected father’s DNA was unavailable. We found significant differences in allele frequencies for seven SNPs in MM subjects compared to ethnically matched reference populations reported in the single nucleotide polymorphism (SNP) database (dbSNP). CONCLUSION We identified a novel variant c.171+3G>T in the MTHFR gene that potentially affects splicing in an affected subject. Also, we observed five SNPs (rs13306561, rs2274976, rs2066462, rs12121543, and rs1476413) in the MTHFR gene not previously shown to associate with MM. The current study provides additional evidence that multiple variations in the MTHFR gene are associated with MM.

Aneji, Chiamaka U; Northrup, Hope; Au, Kit Sing

2012-01-01

348

Population Study of Frequency of Methylenetetrahydrofolate Reductase C677T Gene Polymorphism in Yakutia  

Microsoft Academic Search

The enzyme methylenetetrahydrofolate reductase (MTHFR) catalyzes synthesis of 5'-methylenehydrofolate, which is the methyl donor for the conversion of homocysteine to methionine. According to the numerous literature data, polymorphic variant of the MTHFR-encoding gene, C677T, is associated with hyperhomocysteinemia, vascular pathologies, neural tube defects, dementia, perinatal mortality, mental disorders, long-term neurodegenerative disorders, lens displacement, arachnodactyly, and venous thromboses. The present study

M. G. Spiridonova; V. A. Stepanov; N. R. Maximova; V. P. Puzyrev

2004-01-01

349

5,10-Methylenetetrahydrofolate Reductase Gene Variants and Congenital Anomalies: A HuGE Review  

Microsoft Academic Search

The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) is involved in folate metabolism. The MTHFR gene is located on chromosome 1 (1p36.3), and two common alleles, the C677T (thermolabile) allele and the A1298C allele, have been described. The population frequency of C677T homozygosity ranges from 1% or less among Blacks from Africa and the United States to 20% or more among Italians and

Lorenzo D. Botto; Quanhe Yang

2000-01-01

350

Plasma Total Homocysteine Levels and Methylenetetrahydrofolate Reductase Gene Polymorphism in Patients with Type 2 Diabetes Mellitus  

Microsoft Academic Search

Background: Thrombotic episodes account for approximately 80% of deaths in type 2 diabetic patients. Hyperhomocysteinaemia is a well recognized independent risk factor for atherosclerosis and thromboembolism. Increased homocysteine levels may occur due to a number of factors including inherited gene polymorphism of methylenetetrahydrofolate reductase (MTHFR) C677T. Here, we evaluate plas- ma total homocysteine (tHcy) levels and frequency of the MTHFR

Anna L. Soares; Ana P. Fernandes; Jarbas E. Cardoso; Marinez O. Sousa; Marcelo C. Lasmar; Bethânia A. Novelli; Geralda F. Lages; Luci M. Dusse; Lauro M. Vieira; Bashir A. Lwaleed; Maria G. Carvalho

2009-01-01

351

Methylenetetrahydrofolate reductase gene polymorphisms: genomic predictors of clinical response to fluoropyrimidine-based chemotherapy?  

Microsoft Academic Search

Fluorouracil (5-FU) is widely used in the treatment of colorectal cancer. Methylenetetrahydrofolate reductase (MTHFR) may\\u000a play a central role in the action of 5-FU, an inhibitor of thymidylate synthase, by converting 5,10-methylenetetrahydrofolate\\u000a to 5-methyltetrahydrofolate. The aim of this study was to ascertain whether two polymorphisms in the MTHFR gene (677C>T and\\u000a 1298 A>C) could be used as genomic predictors of

E. Marcuello; A. Altés; A. Menoyo; E. Del Rio; M. Baiget

2006-01-01

352

Lack of association between methylenetetrahydrofolate reductase gene A1298C polymorphism and breast cancer susceptibility  

Microsoft Academic Search

Published data on the association between methylenetetrahydrofolate reductase gene (MTHFR) A1298C polymorphism and breast\\u000a cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Medline,\\u000a PubMed, Embase, and Web of Science were searched. Crude ORs with 95% CIs were used to assess the strength of association between\\u000a the MTHFR A1298C polymorphism and breast

Li-Xin QiuJian; Jian Zhang; Wen-Hua Li; Qun-Ling Zhang; Hui Yu; Bi-Yun Wang; Lei-Ping Wang; Jia-Lei Wang; Hui-Jie Wang; Xiao-Jian Liu; Zhi-Guo Luo; Xiang-Hua Wu

2011-01-01

353

Further evidence that methylenetetrahydrofolate reductase A1298C polymorphism is a risk factor for schizophrenia  

Microsoft Academic Search

Previous work suggests that the methylenetetrahydrofolate reductase gene (MTHFR) functional polymorphism A1298C may be a risk factor for schizophrenia. In this study, the genetic association between the\\u000a MTHFR A1298C polymorphism and schizophrenia was investigated in 379 patients with schizophrenia and 380 age- and sex-matched controls\\u000a subjects. The results showed an association between the 1298C allele and the disorder (OR 1.39,

Chen ZhangBin; Bin Xie; Yasong Du; Wenhong Cheng; Yiru Fang; Shunying Yu

2010-01-01

354

Conversion of Human Steroid 5?-Reductase (AKR1D1) into 3?-Hydroxysteroid Dehydrogenase by Single Point Mutation E120H  

PubMed Central

Human aldo-keto reductase 1D1 (AKR1D1) and AKR1C enzymes are essential for bile acid biosynthesis and steroid hormone metabolism. AKR1D1 catalyzes the 5?-reduction of ?4-3-ketosteroids, whereas AKR1C enzymes are hydroxysteroid dehydrogenases (HSDs). These enzymes share high sequence identity and catalyze 4-pro-(R)-hydride transfer from NADPH to an electrophilic carbon but differ in that one residue in the conserved AKR catalytic tetrad, His120 (AKR1D1 numbering), is substituted by a glutamate in AKR1D1. We find that the AKR1D1 E120H mutant abolishes 5?-reductase activity and introduces HSD activity. However, the E120H mutant unexpectedly favors dihydrosteroids with the 5?-configuration and, unlike most of the AKR1C enzymes, shows a dominant stereochemical preference to act as a 3?-HSD as opposed to a 3?-HSD. The catalytic efficiency achieved for 3?-HSD activity is higher than that observed for any AKR to date. High resolution crystal structures of the E120H mutant in complex with epiandrosterone, 5?-dihydrotestosterone, and ?4-androstene-3,17-dione elucidated the structural basis for this functional change. The glutamate-histidine substitution prevents a 3-ketosteroid from penetrating the active site so that hydride transfer is directed toward the C3 carbonyl group rather than the ?4-double bond and confers 3?-HSD activity on the 5?-reductase. Structures indicate that stereospecificity of HSD activity is achieved because the steroid flips over to present its ?-face to the A-face of NADPH. This is in contrast to the AKR1C enzymes, which can invert stereochemistry when the steroid swings across the binding pocket. These studies show how a single point mutation in AKR1D1 can introduce HSD activity with unexpected configurational and stereochemical preference.

Chen, Mo; Drury, Jason E.; Christianson, David W.; Penning, Trevor M.

2012-01-01

355

Conversion of human steroid 5?-reductase (AKR1D1) into 3?-hydroxysteroid dehydrogenase by single point mutation E120H: example of perfect enzyme engineering.  

PubMed

Human aldo-keto reductase 1D1 (AKR1D1) and AKR1C enzymes are essential for bile acid biosynthesis and steroid hormone metabolism. AKR1D1 catalyzes the 5?-reduction of ?(4)-3-ketosteroids, whereas AKR1C enzymes are hydroxysteroid dehydrogenases (HSDs). These enzymes share high sequence identity and catalyze 4-pro-(R)-hydride transfer from NADPH to an electrophilic carbon but differ in that one residue in the conserved AKR catalytic tetrad, His(120) (AKR1D1 numbering), is substituted by a glutamate in AKR1D1. We find that the AKR1D1 E120H mutant abolishes 5?-reductase activity and introduces HSD activity. However, the E120H mutant unexpectedly favors dihydrosteroids with the 5?-configuration and, unlike most of the AKR1C enzymes, shows a dominant stereochemical preference to act as a 3?-HSD as opposed to a 3?-HSD. The catalytic efficiency achieved for 3?-HSD activity is higher than that observed for any AKR to date. High resolution crystal structures of the E120H mutant in complex with epiandrosterone, 5?-dihydrotestosterone, and ?(4)-androstene-3,17-dione elucidated the structural basis for this functional change. The glutamate-histidine substitution prevents a 3-ketosteroid from penetrating the active site so that hydride transfer is directed toward the C3 carbonyl group rather than the ?(4)-double bond and confers 3?-HSD activity on the 5?-reductase. Structures indicate that stereospecificity of HSD activity is achieved because the steroid flips over to present its ?-face to the A-face of NADPH. This is in contrast to the AKR1C enzymes, which can invert stereochemistry when the steroid swings across the binding pocket. These studies show how a single point mutation in AKR1D1 can introduce HSD activity with unexpected configurational and stereochemical preference. PMID:22437839

Chen, Mo; Drury, Jason E; Christianson, David W; Penning, Trevor M

2012-03-20

356

Methylenetetrahydrofolate reductase gene polymorphisms association with the risk of follicular lymphoma: a meta-analysis.  

PubMed

To date, case-control studies on the association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and follicular lymphoma have provided controversial results. To clarify the effect of MTHFR polymorphisms on the risk of follicular lymphoma, a meta-analysis of all case-control studies was performed. The fixed effects and random effects model showed that the C677T polymorphism was associated with a risk of follicular lymphoma among Caucasian populations, and A1298C polymorphism was associated with a risk of follicular lymphoma among Asian populations. Our pooled data suggest evidence for a major role of MTHFR polymorphisms in the carcinogenesis of follicular lymphoma. PMID:23359274

Xu, Jing-Yan; Sun, Yun-Yu; Zhou, Min; Wang, Jing; Zhang, Qi-Guo; Xu, Xi-Hui; Zeng, Hui; Ouyang, Jian

2013-01-29

357

Development of a Retroviral Construct Containing a Human Mutated Dihydrofolate Reductase cDNA for Hematopoietic Stem Cell Transduction  

Microsoft Academic Search

A double-copy Moloney leukemia virus-based retroviral con- struct containing both the NeoR gene and a mutant human dihydrofolate reductase (DHFR) cDNA (Ser31 mutant) was used to transduce NIH 3T3 and mouse bone marrow (BM) progenitor cells. This resulted in increased resistance of these cells to methotrexate (MTXI. The transduced BM pro- genitor cells were returned to lethally irradiated mice. The

Ming-Xia Li; Debabrata Banerjee; Shi-Cheng Zhao; Barry I. Schweitzer; Shin Mineishi; Eli Gilboa; Joseph R. Bertino

1994-01-01

358

Mutational analysis of the triclosan-binding region of enoyl-ACP (acyl-carrier protein) reductase from Plasmodium falciparum  

Microsoft Academic Search

Triclosan, a known antibacterial, acts by inhibiting enoyl-ACP (acyl-carrier protein) reductase (ENR), a key enzyme of the type II fatty acid synthesis (FAS) system. Plasmodium falciparum, the human malaria-causing parasite, harbours the type II FAS; in contrast, its human host utilizes type I FAS. Due to this striking difference, ENR has emerged as an important target for the devel- opment

Mili KAPOOR; Jayashree GOPALAKRISHNAPAI; Namita SUROLIA; Avadhesha SUROLIA

2004-01-01

359

Mutational and Structural Analyses of the Ribonucleotide Reductase Inhibitor Sml1 Define Its Rnr1 Interaction Domain Whose Inactivation Allows Suppression of mec1 and rad53 Lethality  

PubMed Central

In budding yeast, MEC1 and RAD53 are essential for cell growth. Previously we reported that mec1 or rad53 lethality is suppressed by removal of Sml1, a protein that binds to the large subunit of ribonucleotide reductase (Rnr1) and inhibits RNR activity. To understand further the relationship between this suppression and the Sml1-Rnr1 interaction, we randomly mutagenized the SML1 open reading frame. Seven mutations were identified that did not affect protein expression levels but relieved mec1 and rad53 inviability. Interestingly, all seven mutations abolish the Sml1 interaction with Rnr1, suggesting that this interaction causes the lethality observed in mec1 and rad53 strains. The mutant residues all cluster within the 33 C-terminal amino acids of the 104-amino-acid-long Sml1 protein. Four of these residues reside within an alpha-helical structure that was revealed by nuclear magnetic resonance studies. Moreover, deletions encompassing the N-terminal half of Sml1 do not interfere with its RNR inhibitory activity. Finally, the seven sml1 mutations also disrupt the interaction with yeast Rnr3 and human R1, suggesting a conserved binding mechanism between Sml1 and the large subunit of RNR from different species.

Zhao, Xiaolan; Georgieva, Bilyana; Chabes, Andrei; Domkin, Vladimir; Ippel, Johannes H.; Schleucher, Jurgen; Wijmenga, Sybren; Thelander, Lars; Rothstein, Rodney

2000-01-01

360

Mutational and structural analyses of the ribonucleotide reductase inhibitor Sml1 define its Rnr1 interaction domain whose inactivation allows suppression of mec1 and rad53 lethality.  

PubMed

In budding yeast, MEC1 and RAD53 are essential for cell growth. Previously we reported that mec1 or rad53 lethality is suppressed by removal of Sml1, a protein that binds to the large subunit of ribonucleotide reductase (Rnr1) and inhibits RNR activity. To understand further the relationship between this suppression and the Sml1-Rnr1 interaction, we randomly mutagenized the SML1 open reading frame. Seven mutations were identified that did not affect protein expression levels but relieved mec1 and rad53 inviability. Interestingly, all seven mutations abolish the Sml1 interaction with Rnr1, suggesting that this interaction causes the lethality observed in mec1 and rad53 strains. The mutant residues all cluster within the 33 C-terminal amino acids of the 104-amino-acid-long Sml1 protein. Four of these residues reside within an alpha-helical structure that was revealed by nuclear magnetic resonance studies. Moreover, deletions encompassing the N-terminal half of Sml1 do not interfere with its RNR inhibitory activity. Finally, the seven sml1 mutations also disrupt the interaction with yeast Rnr3 and human R1, suggesting a conserved binding mechanism between Sml1 and the large subunit of RNR from different species. PMID:11074005

Zhao, X; Georgieva, B; Chabes, A; Domkin, V; Ippel, J H; Schleucher, J; Wijmenga, S; Thelander, L; Rothstein, R

2000-12-01

361

Dietary consumption of B vitamins, maternal MTHFR polymorphisms and risk for spontaneous abortion  

PubMed Central

Objective To asses he association between intake of folate and B vitamins and the incidence of spontaneous abortion (SA) according to the maternal methylenetetrahydrofolate reductase (MTHFR) polymorphisms (677 C>T and 1298 A>C). Material and Methods We conducted a nested case-control study within a perinatal cohort of women recruited in the state of Morelos, Mexico. Twenty-three women with SA were compared to 74 women whose pregnancy survived beyond week 20th. Intake of folate and B vitamins respectively, was estimated using a validated food frequency questionnaire. Maternal MTHFR polymorphisms were determined by PCR-RFLP and serum homocysteine levels by HPLC. Results Carriers of MTHFR 677TT and 1298AC genotypes respectively showed an increased risk of SA (OR 677TT vs. CC/CT=5.0; 95% CI: 1.2, 20.9 and OR 1298 AC vs. AA=5.5; 95% CI: 1.1, 26.6). Conclusions Our results support the role of MTHFR polymorphisms as a risk factor for SA, regardless of dietary intake of B vitamins.

Rodriguez-Guillen, Maria del Rosario; Torres-Sanchez, Luisa; Chen, Jia; Galvan-Portillo, Marcia; Silva-Zolezzi, Irma; Blanco-Munoz, Julia; Hernandez-Valero, Maria A.; Lopez-Carrillo, Lizbeth

2010-01-01

362

MTHFR polymorphisms involved in vitamin B12 deficiency associated with atrophic gastritis.  

PubMed

Genetic polymorphisms affecting methylentetrahydrofolate reductase (MTHFR) activity may influence hematological and neurological dysfunction in cobalamin-deficient patients. We studied the prevalence of C677T and A1298C polymorphisms by analyzing genomic DNA in 30 cobalamin-deficient patients. No significant difference was found in 677 and 1298 genotype distribution with respect to hematological parameters, B12 and folate levels, and neurological symptoms. The two MTHFR polymorphisms were not protective against anemia or neurological dysfunction in patients with cobalamin deficiency; however, we found evidence of a significant increase in atrophic gastritis in the 677TT group (P = 0.009) but not for the 1298CC genotype. Based on observations that inadequate cobalamin intake and reduced MTHFR activity might be significant risk factors for gastric cancer, and the increased risk of gastric cancer shown in patients affected by atrophic gastritis, we speculate that concomitant atrophic gastritis and impaired MTHFR function could have a role in the development of gastric cancer. PMID:19521764

Palladino, Mariangela; Chiusolo, Patrizia; Reddiconto, Giovanni; Marietti, Sara; De Ritis, Daniela; Leone, Giuseppe; Sica, Simona

2009-06-12

363

MTHFR T677 homozygosis influences the presence of aura in migraineurs.  

PubMed

It has been suggested that folate metabolism could be involved in migraine pathogenesis. We analysed the 5',10'-methylenetetrahydrofolate reductase (MTHFR) genotypic distribution in a large migraine sample. We genotyped 230 migraine patients (152 migraine without aura (MO) and 78 migraine with aura (MA)) and 204 nonheadache controls. The incidence of TT homozygosis for migraine in general (12%), MO (9%) and MA (18%) did not significantly differ from that found in healthy controls (13%). Differences were significant when the frequency of TT homozygosis between MA and MO (P = 0.03, OR = 2.34, 95% CI = 1.04-5.26) was compared. There was a tendency for a higher frequency of the MTHFR T allele in the MA group (42%) as compared to MO (29%) and controls (36%). These differences were significant only in the case of MA vs. MO (P = 0.006, OR = 1.75, 95% CI = 1.15-2.65). These results could indicate that the MTHFR C677T polymorphism, causing mild hyperhomocystinaemia, might be a genetic risk factor for experiencing aura among migraineurs. Overall, however, there was no association between migraine and the C677T MTHFR polymorphism. PMID:15154859

Oterino, A; Valle, N; Bravo, Y; Muńoz, P; Sánchez-Velasco, P; Ruiz-Alegría, C; Castillo, J; Leyva-Cobián, F; Vadillo, A; Pascual, J

2004-06-01

364

Genetic polymorphisms of methylenetetrahydrofolate reductase and colorectal cancer and adenoma.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating folate metabolism, which affects DNA methylation and synthesis. Two functional, common polymorphisms (C677T and A1298C) are known in the MTHFR gene. MTHFR activity is lowered in individuals with the 677TT genotype and is somewhat reduced in those with the 1298CC genotype. We reviewed the consistency of reported associations of these polymorphisms with colorectal cancer and adenoma with consideration of the effects of nutritional status. A total of 16 studies have addressed the association between MTHFR C677T polymorphism and colorectal cancer in 10 countries. Decreased risk of colorectal cancer associated with the 677TT genotype has fairly consistently been observed, with few exceptions. This decrease was observable in people with either high or low folate status. Alteration in the thymidylate pool associated with MTHFR activity is postulated as an underlying mechanism. Studies on the A1298C polymorphism are limited, and their results are variable. Almost all of seven studies of colorectal adenoma have found no association between C677T polymorphism and adenoma, but the 677TT genotype seems to be related to increased risk when folate status is poor. Reduced availability of methyl groups for DNA methylation might be more relevant to adenoma formation. Although the underlying mechanisms still remain to be clarified, epidemiological findings regarding MTHFR C677T polymorphism provide strong evidence that adequate folate status confers protection from colorectal cancer. PMID:16128738

Kono, Suminori; Chen, Kun

2005-09-01

365

Prevalence of MTHFR C677T and MS A2756G polymorphisms in major depressive disorder, and their impact on response to fluoxetine treatment  

Technology Transfer Automated Retrieval System (TEKTRAN)

To examine the prevalence of the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and the A2756G polymorphism of methionine synthase (MS), and their impact on antidepressant response. We screened 224 subjects (52% female, mean age 39 +/- 11 years) with SCID-diagnosed major...

366

The MTHFR 677C>T polymorphism is associated with an increased risk of hepatocellular carcinoma in patients with alcoholic cirrhosis  

Microsoft Academic Search

Methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate metabolism, plays a major role in the provision of methyl groups for DNA methylation and in the production of dTMP for DNA synthesis. Different poly- morphisms have been described for this enzyme, the most studied being the C677T, which has been shown to be asso- ciated with predisposition to colorectal cancer in

Raphael Saffroy; Patrick Pham; Franck Chiappini; Marine Gross-Goupil; Laurent Castera; Daniel Azoulay; Alain Barrier; Didier Samuel; Brigitte Debuire; Antoinette Lemoine

367

Polymorphisms C677T and A1298C in the MTHFR gene in Mexican patients with rheumatoid arthritis treated with methotrexate: implication with elevation of transaminases  

Microsoft Academic Search

Rheumatoid arthritis (RA) is the prototype of the rheumatic diseases worldwide. Methotrexate (MTX) is the drug of first choice in the treatment of this disease due to its immunosuppressant effect. However, side events are present in 30% of the patients. The C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene are involved in the metabolism of MTX. Earlier studies

J P Mena; M Salazar-Páramo; L González-López; J I Gámez-Nava; L Sandoval-Ramirez; J D Sánchez; L E Figuera; F J Muńoz-Valle; M Vazquez del Mercado; I P Dávalos

2011-01-01

368

Hyperhomocysteinemia and MTHFR C677T and A1298C polymorphisms are associated with chronic allograft nephropathy in renal transplant recipients  

Microsoft Academic Search

Hyperhomocysteine has been reported to be an important risk factor for the development of atherosclerosis. Identification of risk factors, such as hyperhomocysteinemia, is crucial for a better understanding of the events that lead to degenerative processes in the vascular system and for a correct understanding of the potential role of methylene-tetrahydrofolate reductase enzymes (MTHFR) to help in the treatment of

E. C. Pavarino-Bertelli; M. P. Sanches de Alvarenga; E. M. Goloni-Bertollo; M. A. S. F. Baptista; R. Haddad; N. F. Hoerh; M. N. Eberlin; M. Abbud-Filho

2004-01-01

369

Polymorphisms in MTHFR, MS and CBS Genes and Homocysteine Levels in a Pakistani Population  

PubMed Central

Background Hyperhomocysteinemia (>15 µmol/L) is highly prevalent in South Asian populations including Pakistan. In order to investigate the genetic determinants of this condition, we studied 6 polymorphisms in genes of 3 enzymes - methylenetetrahydrofolate reductase (MTHFR; C677T; A1298C), methionine synthase (MS; A2756G), cystathionine-?-synthase (CBS; T833C/844ins68, G919A) involved in homocysteine metabolism and investigated their interactions with nutritional and environmental factors in a Pakistani population. Methodology/Principal Findings In a cross-sectional survey, 872 healthy adults (355 males and 517 females; age 18–60 years) were recruited from a low-income urban population in Karachi. Fasting venous blood was obtained and assessed for plasma/serum homocysteine; folate, vitamin B12, pyridoxal phosphate and blood lead. DNA was isolated and genotyping was performed by PCR-RFLP (restriction-fragment-length- polymorphism) based assays. The average changes in homocysteine levels for MTHFR 677CT and TT genotypes were positive [?(SE ?), 2.01(0.63) and 16.19(1.8) µmol/L, respectively]. Contrary to MTHFR C677T polymorphism, the average changes in plasma homocysteine levels for MS 2756AG and GG variants were negative [?(SE ?), ?0.56(0.58) and ?0.83(0.99) µmol/L, respectively]. The average change occurring for CBS 844ins68 heterozygous genotype (ancestral/insertion) was ?1.88(0.81) µmol/L. The combined effect of MTHFR C677T, MS A2756G and CBS 844ins68 genotypes for plasma homocysteine levels was additive (p value <0.001). Odds of having hyperhomocysteinemia with MTHFR 677TT genotype was 10-fold compared to MTHFR 677CC genotype [OR (95%CI); 10.17(3.6–28.67)]. Protective effect towards hyperhomocysteinemia was observed with heterozygous (ancestral/insertion) genotype of CBS 844ins68 compared to homozygous ancestral type [OR (95% CI); 0.58 (0.34–0.99)]. Individuals with MTHFR 677CT or TT genotypes were at a greater risk of hyperhomocysteinemia in folate and vitamin B12 deficiencies and high blood lead (p value <0.05) level. Conclusions Gene polymorphism (especially MTHFR C677T transition), folate and vitamin B12 deficiencies, male gender and high blood lead level appear to be contributing towards the development of hyperhomocysteinemia in a Pakistani population.

Yakub, Mohsin; Moti, Naushad; Parveen, Siddiqa; Chaudhry, Bushra; Azam, Iqbal; Iqbal, Mohammad Perwaiz

2012-01-01

370

Status of vitamin B-12 and B-6 but not of folate, homocysteine and the methylenetetrahydrofolate reductase C677T polymorphism are associated with impaired cognition and depression in adults  

Technology Transfer Automated Retrieval System (TEKTRAN)

The C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene differs in frequency in different ethnic groups which have differing prevalence of age-related cognitive impairments. We used a battery of neuropsychological tests to examine association of the MTHFR C677T polymorphism w...

371

Methylenetetrahydrofolate reductase polymorphisms, serum methylenetetrahydrofolate reductase levels, and risk of childhood acute lymphoblastic leukemia in a Chinese population.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR), involved in DNA methylation and nucleotide synthesis, is thought to be associated with a decreased risk of adult and childhood acute lymphoblastic leukemia (ALL). Accumulating evidence has indicated that two common genetic variants, C677T and A1298C, are associated with cancer risk. We hypothesized that these two variants were associated with childhood ALL susceptibility and influence serum MTHFR levels. We genotyped these two polymorphisms and detected MTHFR levels in a case-control study of 361 cases and 508 controls. Compared with the 677CC and 677CC/CT genotypes, the 677TT genotype was associated with a statistically significantly decreased risk of childhood ALL (odds ratio = 0.53, 95% confidence interval = 0.32-0.88, and odds ratio = 0.55, 95% confidence interval = 0.35-0.88, respectively). In addition, a pronounced reduced risk of ALL was observed among low-risk ALL and B-phenotype ALL. Moreover, the mean serum MTHFR level was 8.01 ng/mL (+/-4.38) in cases and 9.27 ng/mL (+/-4.80) in controls (P < 0.001). MTHFR levels in subjects with 677TT genotype was significantly higher than those with 677CC genotype (P = 0.010) or 677CT genotype (P = 0.043) in controls. In conclusion, our results provide evidence that the MTHFR polymorphisms might contribute to reduced childhood ALL risk in this population. PMID:20002681

Tong, Na; Fang, Yongjun; Li, Jie; Wang, Meilin; Lu, Qin; Wang, Shizhi; Tian, Yuanyuan; Rong, Liucheng; Sun, Jielin; Xu, Jianfeng; Zhang, Zhengdong

2009-11-11

372

Mutations in the Escherichia coli fnr and tgt genes: control of molybdate reductase activity and the cytochrome d complex by fnr.  

PubMed Central

In eubacteria, the tRNA transglycosylase (Tgt) in specific tRNAs exchanges a guanine in the anticodon for 7-aminomethyl-7-deazaguanine, which is finally converted to queuosine. The tgt gene of Escherichia coli has been mapped at 9 min on the genome, and mutant pairs containing an intact or mutated tgt allele were obtained after transduction of the tgt locus by P1 bacteriophages into a genetically defined E. coli strain (S. Noguchi, Y. Nishimura, Y. Hirota, and S. Nishimura, J. Biol. Chem. 257:6544-6550, 1982). These tgt mutants grew anerobically with fumarate as an electron acceptor, while nitrate or trimethylamine N-oxide could not be reduced. Furthermore, molybdate reductase activity was almost lacking and the characteristic absorption maxima, corresponding to cytochrome a1 and the cytochrome d complex, were not detectable in low-temperature reduced-minus-oxidized difference spectra in anaerobically grown cells. Transduction of the mutated tgt locus into another E. coli recipient resulted in tgt mutants without anaerobic defects. Transformation of the original tgt mutants with an fnr gene-containing plasmid reversed the anaerobic defects. Clearly, the original tgt mutants harbor a second mutation, affecting the anaerobic regulator protein Fnr. The results suggest that fnr is involved in anaerobic control of components of the cytochrome d complex and of the redox system that transfers electrons to molybdate. F' plasmids containing a fused lacI-lacZ gene with the nonsense codon UAG at different positions in the lacI part were transferred to E. coli strains with a mutated or nonmutated tgt locus but intact in fnr. A twofold increase in the frequency of incorrect readthrough of the UAG codon, dependent on the codon context, was observed in the tgt mutant and is suggested to be caused by a tRNA(Tyr) with G in place of queuosine.

Frey, B; Janel, G; Michelsen, U; Kersten, H

1989-01-01

373

Strain-specific defects in testicular development and sperm epigenetic patterns in 5,10-methylenetetrahydrofolate reductase-deficient mice.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) is a crucial folate pathway enzyme that contributes to the maintenance of cellular pools of S-adenosylmethionine, the universal methyl donor for several reactions including DNA methylation. Whereas Mthfr(-/-) BALB/c mice show growth retardation, developmental delay, and spermatogenic defects and infertility, C57BL/6 mice appear to have a less severe phenotype. In the present study, we investigated the effects of MTHFR deficiency on early germ cell development in both strains and assessed whether MTHFR deficiency results in DNA methylation abnormalities in sperm. The reproductive phenotype associated with MTHFR deficiency differed strikingly between the two strains, with BALB/c mice showing an early postnatal loss of germ cell number and proliferation that was not evident in the C57BL/6 mice. As a result, the BALB/c MTHFR-deficient mice were infertile, whereas the C57BL/6 mice had decreased sperm numbers and altered testicular histology but showed normal fertility. Imprinted genes and sequences that normally become methylated during spermatogenesis were unaffected by MTHFR deficiency in C57BL/6 mice. In contrast, a genome-wide restriction landmark genomic scanning approach revealed a number of sites of hypo- and hypermethylation in the sperm of this mouse strain. These results showing strain-specific defects in MTHFR-deficient mice may help to explain population differences in infertility among men with common MTHFR polymorphisms. PMID:20444942

Chan, Donovan; Cushnie, Duncan W; Neaga, Oana R; Lawrance, Andrea K; Rozen, Rima; Trasler, Jacquetta M

2010-05-05

374

DNA strand-specific mutations induced by (+)-3. alpha. ,4. beta. -dihydroxy-1. alpha. ,2. alpha. -epoxy-1,2,3,4-tetrahydrobenzo(c)phenanthrene in the dihydrofolate reductase gene  

Microsoft Academic Search

The authors previously showed that the preferred mutation induced by ({plus minus})-3α,4β-dihydroxy-1α,2α-epoxy-1,2,3,4-tetrahydrobenzo(c)phenanthrene (BcPHDE) in the dihydrofolate reductase gene in Chinese hamster ovary cells was a purine to thymine transversion on the nontranscribed strand at the sequence 5â˛-{und R}RR-3Ⲡ(R is a purine and the mutated base is underlined). To determine whether the observed mutational strand specificity was due to bias

A. M. Carothers; J. Mucha; D. Grunberger

1991-01-01

375

Infants' MTHFR polymorphisms and nonsyndromic orofacial clefts susceptibility: a meta-analysis based on 17 case-control studies.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR), an important enzyme in folate metabolism, is thought to be involved in the development of nonsyndromic orofacial clefts (NSOC). However, conflicting results have been achieved when evaluating the associations between infants' MTHFR C677T and A1298C polymorphisms and the risk of NSOC. To obtain more precise estimations of these associations, a meta-analysis recruiting 17 case-control studies was performed. Among Asians we found that CT heterozygote, TT homozygote, and CT/TT of infants' MTHFR C677T variant could contribute to elevated risks of NSOC, compared with CC wild-type homozygote (OR=1.741, 95% CI=1.043-2.907 for CT vs. CC, OR=2.311, 95% CI=1.313-4.041 for TT vs. CC, and OR=1.740, 95% CI=1.051-2.882 for CT/TT vs. CC, respectively). Similar effect was also observed on MTHFR 677T T allele, when using C allele as a reference in Asians (OR=1.420, 95% CI=1.191-1.693, for T allele vs. C allele). Furthermore, in stratified analysis by types of disease, CT/CC was suggested to confer decreased susceptibility to CL/P under recessive genetic model (OR=0.854, 95% CI=0.730-1.000). For MTHFR A1298C, the MTHFR 1298C allele in the case group of Caucasians was significantly lower than that in the control group, suggesting a protective effect against NSOC in Caucasian populations (OR=0.711, 95% CI=0.641-0.790, for C allele vs. A allele). In conclusion, the meta-analysis provided confirmative evidences that infants' MTHFR C677T and A1298C polymorphisms were involved in the development of NSOC. PMID:22847888

Pan, Yongchu; Zhang, Weibing; Ma, Junqing; Du, Yifei; Li, Dandan; Cai, Qi; Jiang, Hongbing; Wang, Meilin; Zhang, Zhengdong; Wang, Lin

2012-07-27

376

MTHFR C677T Polymorphism and Risk of Congenital Heart Defects: Evidence from 29 Case-Control and TDT Studies  

PubMed Central

Background Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme for folate metabolism in humans; it is encoded by the MTHFR gene. Several studies have assessed the association between MTHFR C677T polymorphism and the risk of congenital heart defects (CHDs), while the results were inconsistent. Methods and Findings Multiple electronic databases were searched to identify relevant studies published up to July 22, 2012. Data from case-control and TDT studies were integrated in an allelic model using the Catmap and Metafor software. Twenty-nine publications were included in this meta-analysis. The overall meta-analysis showed significant association between MTHFR C677T polymorphism and CHDs risk in children with heterogeneity (Pheterogeneity?=?0.000) and publication bias (Pegger?=?0.039), but it turned into null after the trim-and-fill method was implemented (OR?=?1.12, 95% CI?=?0.95–1.31). Nevertheless, positive results were obtained after stratified by ethnicity and sample size in all subgroups except the mixed population. For mothers, there was significant association between the variant and CHDs without heterogeneity (Pheterogeneity?=?0.150, OR?=?1.16, 95% CI?=?1.05–1.29) and publication bias (Pegger?=?0.981). However, the results varied across each subgroup in the stratified analysis of ethnicity and sample size. Conclusions Both infant and maternal MTHFR C677T polymorphisms may contribute to the risk of CHDs.

Gong, Fangqi; Zhu, Weihua; Fu, Songling

2013-01-01

377

Methotrexate-induced mucositis in acute leukemia patients is not associated with the MTHFR 677T allele in Mexico.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) has two common variants with reduced activity due to polymorphisms at nucleotides 677 and 1298. Both affect folate metabolism and thus remethylation of homocysteine, but are also thought to affect nucleotide synthesis and DNA methylation. Methotrexate (MTX), which interrupts folate metabolism, is used in the treatment of a variety of diseases including acute lymphoblastic leukemia (ALL), but exerts in some patients toxic effects on fast dividing tissues such as mucosal epithelia. The enhanced toxicity may be due to cooperative effects between MTX and MTHFR variants. Accordingly, it has been reported that carrying the 677T allele of the MTHFR is a risk factor for MTX-associated mucositis. As in the Mexican population, which is characterized by a high prevalence of the 677T MTHFR variant, several of its commonly associated defects have not been observed, we investigated the relationship between MTX toxicity and the 677T allele. Out of 28 patients with ALL (CC: 2, CT: 10, TT: 16), 16 had episodes of MTX-associated mucositis (CC: 0, CT: 6, TT: 10). Neither at the gene level nor at the genotype level was a significant association with mucositis found. It may be postulated that the risk of higher MTX toxicity in patients with decreased MTHFR activity could be neutralized by the normally folate rich diet in Mexico. PMID:17891601

Ruiz-Argüelles, Guillermo J; Coconi-Linares, Lucia Nancy; Garcés-Eisele, Javier; Reyes-Núńez, Virginia

2007-10-01

378

Dietary intake of folate and co-factors in folate metabolism, MTHFR polymorphisms, and reduced rectal cancer  

PubMed Central

Little is known about the contribution of polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR) and the folate metabolism pathway in rectal cancer alone. Data were from participants in a case-control study conducted in Northern California and Utah (751 cases and 979 controls). We examined independent associations and interactions of folate, B vitamins, methionine, alcohol, and MTHFR polymorphisms (MTHFR C677T and A1298C) with rectal cancer. Dietary folate intake was associated with a reduction in rectal cancer OR 0.66, 95% CI 0.48-0.92 (>475 mcg day compared to < = 322 mcg) as was a combination of nutrient intakes contributing to higher methyl donor status (OR 0.79, 95% CI 0.66-0.95). Risk was reduced among women with the 677 TT genotype (OR 0.54, 95% CI 0.30-0.9), but not men (OR 1.11, 95% CI 0.70-1.76) and with the 1298 CC genotype in combined gender analysis (OR 0.67, 95% CI 0.46-0.98). These data are consistent with a protective effect of increasing dietary folate against rectal cancer and suggest a protective role of the MTHFR 677 TT genotype in women and 1298 CC in men and women. Folate intake, low methyl donor status, and MTHFR polymorphisms may play independent roles in the etiology of rectal cancer.

Murtaugh, Maureen A.; Curtin, Karen; Sweeney, Carol; Wolff, Roger K.; Holubkov, Richard; Slattery, Martha L.; Caan, Bette J.

2008-01-01

379

Polymorphisms in the MTHFR gene and their possible association with susceptibility to childhood acute lymphocytic leukemia in an Indian population.  

PubMed

Acute lymphocytic leukemia (ALL) is the most common pediatric cancer worldwide, and is particularly more common in the Indian population. Hence, research is increasingly examining the factors involved in disease development. In the present study, we examined the effect of MTHFR (5,10-methylenetetrahydrofolate reductase) C677T and A1298C polymorphisms in ALL. Blood samples of 135 children with ALL and 142 matched controls were analysed. The presence of MTHFR C677T and A1298C polymorphisms were screened using polymerase chain reaction-restriction fragment length polymorphism based approaches. The frequency of MTHFR 677CC, 677CT and 677TT genotypes were 37.77%, 57.03% and 5.18% in cases and 55.63%, 40.84% and 3.52% in controls, respectively. Frequencies of MTHFR 1298AA, 1298AC and 1298CC genotypes were 30.37%, 61.48% and 8.14% in cases and 45.77%, 47.88% and 6.33% in controls, respectively. The present study inidcates that there is an association between MTHFR gene polymorphisms and ALL. MTHFR variants also showed a gender bias. The frequencies of MTHFR 677CC and 677CT genotypes were 33.33% and 65.51% in males and 45.83% and 41.66% in females. Frequencies of MTHFR 1298AA, 1298AC and 1298CC genotypes were 26.43%, 67.81% and 5.74% in males and 37.5%, 50.0% and 12.5% in females, respectively. It is evident that the male children were more susceptible to ALL compared to female children. Associations found in these studies were significant with respect to gender bias; hence, it is possible that MTHFR C677T and A1298C can be good markers for ALL. Moreover, the possibility also exists that these variants may be influenced by the folate uptake of mothers during pregnancy, thereby influencing the enzyme activity and the ethnicity of the cases examined to date. The gender bias of MTHFR polymorphism in ALL is reported for the first time. PMID:16923565

Reddy, Haranatha; Jamil, Kaiser

2006-07-01

380

Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease.  

PubMed

Severe methylenetetrahydrofolate reductase (MTHFR) deficiency with less than 2% of normal enzyme activity is characterized by neurological abnormalities, atherosclerotic changes, and thromboembolism. We have discovered a "new" variant of MTHFR deficiency which is characterized by the absence of neurological abnormalities, an enzyme activity of about 50% of the normal value, and distinctive thermolability under specific conditions of heat inactivation. In this study, lymphocyte MTHFR specific activities in the thermolabile variant and control groups were 5.58 +/- 0.91 and 10.33 +/- 2.89 nmol formaldehyde formed/mg protein/h, respectively. The difference was significant (P less than .01). However, there was overlap among the individual values from the two groups. On the other hand, residual MTHFR activity after heat inactivation was 11.2 +/- 1.43% in the thermolabile variant and 36.3 +/- 5.18% in the controls. There was no overlap. Enzyme studies in 10 subjects with thermolabile MTHFR and their family members support the hypothesis that thermolabile MTHFR is inherited as an autosomal recessive trait. To elucidate the association of thermolabile MTHFR with the development of coronary artery disease, we determined the thermostability of lymphocyte MTHFR in 212 patients with proven coronary artery disease and in 202 controls without clinical evidence of atherosclerotic vascular disease. Thermolabile MTHFR was found in 36 (17.0%) cardiac patients and 10 (5.0%) controls. The difference in incidence between the two groups was statistically significant (P less than .01). The average age at onset of clinical coronary artery disease in 36 patients with thermolabile MTHFR was 57.3 +/- 7.6 years (35-72 years). The mean total plasma homocysteine concentration in patients with thermolabile MTHFR was 13.19 +/- 5.32 nmol/ml and was significantly different from the normal mean of 8.50 +/- 2.80 nmol/ml (P less than .05). There was no association between thermolabile MTHFR and other major risk factors. We conclude that thermolabile MTHFR is a variant(s) of MTHFR deficiency which is inherited as an autosomal recessive trait. In addition, it is positively associated with the development of coronary artery disease. Determination of in vitro thermostability of lymphocyte MTHFR is a reliable method for identifying subjects with this abnormality. PMID:1998339

Kang, S S; Wong, P W; Susmano, A; Sora, J; Norusis, M; Ruggie, N

1991-03-01

381

Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease.  

PubMed Central

Severe methylenetetrahydrofolate reductase (MTHFR) deficiency with less than 2% of normal enzyme activity is characterized by neurological abnormalities, atherosclerotic changes, and thromboembolism. We have discovered a "new" variant of MTHFR deficiency which is characterized by the absence of neurological abnormalities, an enzyme activity of about 50% of the normal value, and distinctive thermolability under specific conditions of heat inactivation. In this study, lymphocyte MTHFR specific activities in the thermolabile variant and control groups were 5.58 +/- 0.91 and 10.33 +/- 2.89 nmol formaldehyde formed/mg protein/h, respectively. The difference was significant (P less than .01). However, there was overlap among the individual values from the two groups. On the other hand, residual MTHFR activity after heat inactivation was 11.2 +/- 1.43% in the thermolabile variant and 36.3 +/- 5.18% in the controls. There was no overlap. Enzyme studies in 10 subjects with thermolabile MTHFR and their family members support the hypothesis that thermolabile MTHFR is inherited as an autosomal recessive trait. To elucidate the association of thermolabile MTHFR with the development of coronary artery disease, we determined the thermostability of lymphocyte MTHFR in 212 patients with proven coronary artery disease and in 202 controls without clinical evidence of atherosclerotic vascular disease. Thermolabile MTHFR was found in 36 (17.0%) cardiac patients and 10 (5.0%) controls. The difference in incidence between the two groups was statistically significant (P less than .01). The average age at onset of clinical coronary artery disease in 36 patients with thermolabile MTHFR was 57.3 +/- 7.6 years (35-72 years). The mean total plasma homocysteine concentration in patients with thermolabile MTHFR was 13.19 +/- 5.32 nmol/ml and was significantly different from the normal mean of 8.50 +/- 2.80 nmol/ml (P less than .05). There was no association between thermolabile MTHFR and other major risk factors. We conclude that thermolabile MTHFR is a variant(s) of MTHFR deficiency which is inherited as an autosomal recessive trait. In addition, it is positively associated with the development of coronary artery disease. Determination of in vitro thermostability of lymphocyte MTHFR is a reliable method for identifying subjects with this abnormality.

Kang, S S; Wong, P W; Susmano, A; Sora, J; Norusis, M; Ruggie, N

1991-01-01

382

Associations of MTHFR and MTRR Polymorphisms With Serum Lipid Levels in Chinese Hypertensive Patients.  

PubMed

Objective: To examine the effects of the methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) gene polymorphisms and their interactions with environmental factors on serum lipid levels. Methods: We investigated totally 340 patients with essential hypertension, from Dongzhi community, Anhui, China. High-throughput TaqMan allelic discrimination assay was used for the genotyping of MTHFR C677T (Ala222Val), MTHFR A1298C (Glu429Ala), MTRR A66G (Ile22Met), and MTRR His595Tyr. Results: Compared with the MTRR 66AA genotype carriers, the GG genotype carriers had lower serum total cholesterol (TC) levels (adjusted ? ± standard error [SE]: -0.5 ± 0.2 mmol/L; P = .003) and low-density lipoprotein cholesterol (LDL-C) levels (adjusted ? ± SE: -0.4 ± 0.2 mmol/L; P = .005). Their false discovery rate (FDR)-adjusted P values were 0.056 and 0.056, respectively. We further found that there was a statistically significant interaction between 677TT genotype and sex in their associations with LDL levels (P interaction = .020), and significant interaction between 677TT genotype and smoking on LDL levels (P interaction = .036). A similar pattern of interaction was found between 66GG and drinking on levels of TC (P interaction = .034) and LDL (P interaction = .020). However, there were no significant interactions observed after FDR adjustment. Conclusion: Both MTHFR and MTRR gene polymorphisms could be important genetic determinants of serum lipid levels in Chinese patients with hypertension. These findings need to be replicated in a larger sample. PMID:23188888

Jiang, Shanqun; Zhao, Ruimeng; Pan, Mingluo; Venners, Scott A; Zhong, Guisheng; Hsu, Yi-Hsiang

2012-11-26

383

MTHFR C677T and A1298C polymorphisms are risk factors for Down’s syndrome in Indian mothers  

Microsoft Academic Search

Downs syndrome (DS), a chromosomal disorder due to trisomy 21, results mostly from nondisjunction in maternal meiosis. The present case-control study examined the association of genetic polymorphisms with predisposition to nondisjunction. Two common polymorphisms (SNPs), C677T and A1298C, in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene involved in folate metabolism, are known to lower the activity of this enzyme. Three hundred and

Amit Kumar Rai; Satya Singh; Stuti Mehta; Ashok Kumar; L. K. Pandey; Rajiva Raman

2006-01-01

384

Increased prevalence of combined MTR and MTHFR genotypes among individuals with severely elevated total homocysteine plasma levels  

Microsoft Academic Search

The prevalence of the methionine synthase (MTR) 2756A?G polymorphism among individuals with severely elevated total homocysteine (tHcy) plasma levels is unknown. Therefore, 1,716 subjects, including 415 hemodialysis patients, 179 peritoneal dialysis patients, 733 kidney graft recipients, and 389 healthy subjects, were investigated. The distribution of MTR 2756A?G, as well as 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C?T\\/1298A?C, genotypes among study participants with extremely

Alexandra Feix; Robert Fritsche-Polanz; Josef Kletzmayr; Andreas Vychytil; Walter H. Hörl; Gere Sunder-Plassmann; Manuela Födinger

2001-01-01

385

C677T and A1298C MTHFR polymorphisms, a challenge for antifolate and fluoropyrimidine-based therapy personalisation  

Microsoft Academic Search

Pharmacogenetics represents an exciting, new promising tool for the individualisation of therapy. Several genetic polymorphisms and haplotypes have been considered in an attempt to optimise therapy with specific drugs but, up to now, their clinical applications remain limited.5,10-Methylenetetrahydrofolate reductase (MTHFR), a key enzyme of one-carbon metabolism, catalyses the irreversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. Two common non-synonymous variants, the C677T

Elena De Mattia; Giuseppe Toffoli

2009-01-01

386

Epistasis between COMT and MTHFR in Maternal-Fetal Dyads Increases Risk for Preeclampsia  

PubMed Central

Preeclampsia is a leading cause of perinatal morbidity and mortality. This disorder is thought to be multifactorial in origin, with multiple genes, environmental and social factors, contributing to disease. One proposed mechanism is placental hypoxia-driven imbalances in angiogenic and anti-angiogenic factors, causing endothelial cell dysfunction. Catechol-O-methyltransferase (Comt)-deficient pregnant mice have a preeclampsia phenotype that is reversed by exogenous 2-methoxyestradiol (2-ME), an estrogen metabolite generated by COMT. 2-ME inhibits Hypoxia Inducible Factor 1?, a transcription factor mediating hypoxic responses. COMT has been shown to interact with methylenetetrahydrofolate reductase (MTHFR), which modulates the availability of S-adenosylmethionine (SAM), a COMT cofactor. Variations in MTHFR have been associated with preeclampsia. By accounting for allelic variation in both genes, the role of COMT has been clarified. COMT allelic variation is linked to enzyme activity and four single nucleotide polymorphisms (SNPs) (rs6269, rs4633, rs4680, and rs4818) form haplotypes that characterize COMT activity. We tested for association between COMT haplotypes and the MTHFR 677 C?T polymorphism and preeclampsia risk in 1103 Chilean maternal-fetal dyads. The maternal ACCG COMT haplotype was associated with reduced risk for preeclampsia (P?=?0.004), and that risk increased linearly from low to high activity haplotypes (P?=?0.003). In fetal samples, we found that the fetal ATCA COMT haplotype and the fetal MTHFR minor “T” allele interact to increase preeclampsia risk (p?=?0.022). We found a higher than expected number of patients with preeclampsia with both the fetal risk alleles alone (P?=?0.052) and the fetal risk alleles in combination with a maternal balancing allele (P<0.001). This non-random distribution was not observed in controls (P?=?0.341 and P?=?0.219, respectively). Our findings demonstrate a role for both maternal and fetal COMT in preeclampsia and highlight the importance of including allelic variation in MTHFR.

Hill, Lori D.; York, Timothy P.; Kusanovic, Juan P.; Gomez, Ricardo; Eaves, Lindon J.; Romero, Roberto; Strauss, Jerome F.

2011-01-01

387

MTHFR C677T and A1298C polymorphisms: diet, estrogen, and risk of colon cancer.  

PubMed

5,10-methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism, diverting metabolites toward methylation reactions or nucleotide synthesis. Using data from an incident case-control study (1608 cases and 1972 controls) we investigated two polymorphisms in the MTHFR gene, C677T and A1298C, and their associations with risk of colon cancer. All of the combined genotypes were evaluated separately, and the 1298AA/677CC (wild-type/wild-type) group was considered the reference group. Among both men and women, the 677TT/1298AA (variant/wild-type) genotype was associated with a small reduction in risk [men: odds ratio (OR), 0.7, 95% confidence interval (CI), 0.5-1.0; women: OR, 0.8, 95% CI, 0.5-1.2]. However, the 677CC/1298CC (wild-type/variant) genotype was associated with a statistically significant lower risk among women (OR, 0.6; 95% CI, 0.4-0.9) but not men. When the polymorphisms were considered individually, for A1298C a significant risk reduction associated with the homozygous variant CC genotype was seen among women only (OR, 0.6; 95% CI, 0.5-0.9), and nonstatistically significant reduced risks were observed for the variant 677 TT genotypes among both men and women. Stratification by nutrient intakes showed inverse associations with higher intakes of folate, vitamin B(2), B(6), B(12), and methionine among women with the MTHFR 677CC/1298AA genotypes, but not those with 677TT/1298AA. We observed opposite risk trends for both MTHFR variants, depending on whether women used hormone-replacement therapy or not (P for interaction = <.01). In summary, this study supports recent findings that the MTHFR A1298C polymorphism may be a predictor of colon cancer risk and have functional relevance. The possible interaction with hormone-replacement therapy warrants additional investigation. PMID:14973104

Curtin, Karen; Bigler, Jeannette; Slattery, Martha L; Caan, Bette; Potter, John D; Ulrich, Cornelia M

2004-02-01

388

[The role of homocysteine and methylenetetrahydrofolate reductase, methionine synthase, methionine synthase reductase polymorphisms in the development of cardiovascular diseases and hypertension].  

PubMed

Cardiovascular diseases (CVDs) are the leading causes of death in the developed countries. Elevated homocysteine level is as an independent risk factor of CVDs. The C677T and A1298C variants of methylenetetrahydrofolate reductase gene (MTHFR) have been shown to influence folate and homocysteine metabolisms. However, the relationship between MTHFR polymorphisms and hyperhomocysteinemia has not been well established yet. The gene variants were also reported to be associated with CVDs. In addition, the C677T polymorphisms may play a role in the development of hypertension. Recent research evidence has suggested that MTHFR variants might be independently linked to CVDs and hypertension, because of the involvement of the MTHFR enzyme product (5-methyl-tetrahydrofolate /5-MTHF) in the regulation of endothelial functions. Further research is required to investigate the association between gene polymorphisms of folate-metabolizing enzymes and CVDs, and to identify the possible role of the relevant gene variants in the molecular pathogenesis of hyperhomocysteinemia. PMID:22411217

Marosi, Krisztina; Agota, Annamária; Végh, Veronika; Joó, József Gábor; Langmár, Zoltán; Kriszbacher, Ildikó; Nagy, Zsolt B

2012-03-25

389

Identification of three new mutations in the NADH-cytochrome b5 reductase gene responsible for recessive congenital methemoglobinemia type II  

SciTech Connect

Recessive congenital methemoglobinemia (RCM; McKusick N{degrees}25800) due to NADH-cytochrome b5 reductase (cytb5r) deficiency leads to two different types of diseases: in type I form, cyanosis is the only symptom and the enzyme is only defective in red blood cells; in type II form, cyanosis is associated with severe mental retardation and neurological impairment and the enzyme defect is systemic. We have identified three new molecular defects in two unrelated patients with type II RCM. A homozygous C{r_arrow}T transition in codon 218 (Arg) was detected in the cDNA of one patient, resulting in a premature stop codon (TGA) in exon 8. Restriction enzyme analysis of genomic DNA confirmed the homozygosity of the propositus and heterozygosity for an identical defect in both parents. The second patient was found to be a compound heterozygote, carrying two different mutant alleles in the cyb5r gene. One allele presented a missense mutation (T{r_arrow}C) with substitution of Cys-203 (TGC) by Arg (CGC) in exon 7. The second allele showed a 3 bp deletion of nucleotides 815-817 of the cDNA. The CTG ATG sequence at position 814-819 in exon 9 coding for Leu-271 and Met-272 was replaced by the CTG triplet, with conservation of the Leu-271 and loss of the Met-272. To our knowledge, these are the first examples of a homozygous nonsense mutation and of a compound heterozygous mutation detected in the cytb5r gene. This finding supports the diversity of genetic defects in the cytb5r gene leading to the severe form of the disease.

Mota-Vieira, L.; Kaplan, J.C.; Kahn, A.; Leroux, A. [Universite Rene Descartes-Paris (France)

1994-09-01

390

Methionine synthase A2756G and methylenetetrahydrofolate reductase A1298C polymorphisms are not risk factors for idiopathic venous thromboembolism  

Microsoft Academic Search

Hyperhomocysteinemia is a defined risk factor for venous thromboembolism (VTE). Several polymorphisms of genes encoding for enzymes acting in the remethylation pathway of homocysteine metabolism, ie, methionine synthase (MS) A2756G, methylenetetrahydrofolate reductase (MTHFR) C677T and MTHFR A1298C, can cause increased homocysteine levels particularly in patients with deficiencies of folic acid, vitamin B6, or B12 and hence be potential risk factors

Ophira Salomon; Nurit Rosenberg; Ariella Zivelin; David M Steinberg; Nurit Kornbrot; Rima Dardik; Aida Inbal; Uri Seligsohn

2001-01-01

391

Homocysteine and methylenetetrahydrofolate reductase C677T and A1298C polymorphisms in Tunisian patients with severe coronary artery disease  

Microsoft Academic Search

Elevation in homocysteine and methylenetetrahydrofolate reductase (MTHFR) gene variants, C677T and A1298C, have been linked\\u000a with atherothrombosis. However their exact contribution to coronary artery disease (CAD) remains controversial. Moreover,\\u000a data from Tunisian patients are scarse. We examined the association of MTHFR C677T and A1298C, and changes in plasma homocysteine\\u000a in 352 Tunisian patients with angiographically-demonstrated CAD, and 390 age and

Lakhdar Ghazouani; Nesrine Abboud; Nabil Mtiraoui; Walid Zammiti; Faouzi Addad; Haitham Amin; Wassim Y. Almawi; Touhami Mahjoub

2009-01-01

392

Genotyping of two single nucleotide polymorphisms in 5,10-methylenetetrahydrofolate reductase by multiplex polymerase chain reaction and capillary electrophoresis  

Microsoft Academic Search

Two single nucleotide polymorphisms (SNPs) of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, A1298C and C677T, were widely considered to be related with various neoplasia disorders. We established a simple and effective capillary electrophoresis (CE) method for detection of two SNPs in MTHFR gene simultaneously. DNA samples were amplified by multiplex PCR with universal fluorescence-labeled primer and analyzed by single-strand conformation polymorphism (SSCP)-CE

Hui-Ling Cheng; Shyh-Shin Chiou; Yu-Mei Liao; Yen-Ling Chen; Shou-Mei Wu

2011-01-01

393

Plasma homocysteine, methylene tetrahydrofolate reductase C677T and factor II G20210A polymorphisms, factor VIII, and VWF in central retinal vein occlusion  

PubMed Central

AIMS—To determine whether plasma homocysteine, methylene tetrahydrofolate reductase (MTHFR) C677T and factor II G20210A polymorphisms, factor VIII, and vWF are risk factors for central retinal vein occlusion (CRVO).?METHOD—Prospective comparison of 63 consecutive patients with central retinal vein occlusion and 63 age matched controls. Plasma homocysteine and vWF were estimated by ELISA, the MTFHR and factor II G20210A polymorphisms determined by polymerase chain reaction with restriction enzyme product digestion and factor VIII by one stage automated clotting assay.?RESULTS—Plasma homocysteine (patients: median 12.4 µmol/l, controls: median 11.6 µmol OR = 1.05, p=0.20), factor VIII (patients: median = 115 U/dl, controls: median = 113 U/dl), and vWF (patients: median = 115 U/dl, controls: median = 108 U/dl) were not statistically higher in patients than in controls. Five CRVO patients and seven controls were homozygous for the MTHFR C677T mutation. One control was heterozygous for the factor II G20210A mutation.?CONCLUSION—This study has not identified new risk factors for CRVO.??

Boyd, S; Owens, D; Gin, T; Bunce, K; Sherafat, H; Perry, D; Hykin, P

2001-01-01

394

Increased neurotoxicity of arsenic in methylenetetrahydrofolate reductase deficiency.  

PubMed

A 16-year-old girl from Surinam presented with mental deterioration and severe paraparesis with areflexia and bilateral Babinski signs. Laboratory examination showed a hyperhomocysteinemia that was caused by 5,10-methylene-tetrahydrofolate reductase (MTHFR) deficiency. In addition, urine samples contained large amounts of arsenic. An open bag with the pesticide copper acetate arsenite was found to be the source of exposure. In remethylation defects such as MTHFR deficiency, the concentration of methyldonors is severely reduced. As arsenic is detoxified by methylation, we suggest that the MTHFR deficiency in this girl might explain the fact that of all family members exposed to arsenic, only she developed severe clinical signs and symptoms of arsenic poisoning. PMID:1335858

Brouwer, O F; Onkenhout, W; Edelbroek, P M; de Kom, J F; de Wolff, F A; Peters, A C

1992-01-01

395

Prevalence of hyperhomocysteinemia and the MTHFR C677T polymorphism in patients with arterial and venous thrombosis from North Western Russia.  

PubMed

Conflicting data from Western European and USA population studies led us to investigate hyperhomocysteinemia (HHcy), the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms and thrombotic disease in North Western Russia. Plasma total homocysteine (tHcy) levels, MTHFR C677T genotype, selected life style determinants and haemostatic factor activity were determined in patients with arterial (n = 33), venous (n = 40), arterial + venous (n = 11) thrombosis and healthy controls (n = 30). We found raised median tHcy levels in all patient groups vs. controls (p < 0.05), with odds ratios (95% CI) for vascular disease among patients with HHcy (defined as > 15 micromol/l) of 3.9 (0.6 - 14.3), 4.8 (1.2 - 18.8) and 15.8 (2.8 - 87.3) respectively. tHcy levels were a function of MTHFR C677T genotype, and all patients with tHcy levels > 30 micromol/l had the MTHFR C677T homozygous substitution. Elevated tHcy levels (p < 0.05) were identified in smokers and coffee drinkers, with the degree of elevation dependent on MTHFR C677T genotype. Of the studied haemostatic parameters increased factor VIII activity and vWF antigen and activity was observed in HHcy subjects. We conclude that HHcy and MTHFR C677T genotype are positively associated with arterial and venous thrombotic disease in the population of North Western Russia. PMID:14698652

Shmeleva, Veronika M; Kapustin, Sergey I; Papayan, Ludmila P; Sobczy?ska-Malefora, Agata; Harrington, Dominic J; Savidge, Geoffrey F

2003-01-01

396

Genetic polymorphisms of MTHFR and aberrant promoter hypermethylation of the RASSF1A gene in bladder cancer risk in a Chinese population.  

PubMed

Epidemiological studies have shown that folate deficiency increases the risk of cancer by affecting DNA repair and methylation. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism. In this study, it was hypothesized that MTHFR (C677T and A1298C) polymorphisms would be associated with bladder cancer and also with hypermethylation of the promoter of the Ras association domain family 1A (RASSF1A) gene. This hospital-based, case-control study of 312 bladder cancer patients and 325 cancer-free controls found that individuals carrying the MTHFR 677TT genotype had a 2.00-fold increased risk of bladder cancer compared with those carrying the 677CC genotype. None of the MTHFR A1298C polymorphisms alone were associated with bladder cancer, but the combined haplotype 677TT/1298AA was associated with a 2.27-fold increased risk compared with haplotype 677CC/1298AA. There was no association between MTHFR gene variants and methylation status of the RASSF1A gene in the 45 bladder cancer patients in whom this was studied. It is concluded that the MTHFR 677TT genotype and the TTAA haplotype may increase the risk of bladder cancer. PMID:20146887

Cai, D W; Liu, X F; Bu, R G; Chen, X N; Ning, L; Cheng, Y; Wu, B

397

MTHFR C677T and A1298C variant genotypes and the risk of microsatellite instability among Iranian colorectal cancer patients  

PubMed Central

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the folate metabolic pathway. We aimed to test the hypothesis that C677T and A1298C variants of MTHFR predispose to microsatellite instable (MSI) colorectal cancer. We determined MTHFR genotypes in 175 sporadic colorectal cancer patients and a total of 231 normal controls in Shiraz, Southern Iran. Among the genotypes found in our samples, MTHFR CT and CT + TT were associated with increased risk for CRC incidence [odds ratio (OR) = 2.4, 95% confidence interval (95%CI) = 1.8–4.4; OR = 2.4, 95%CI = 1.6–3.6, respectively]. Double heterozygotes 677CT/1298AC and double homozygote 677TT/1298AA and 677CC/1298CC genotypes also showed a significantly increased risk of developing CRC compared with the wild