Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Venous thromboembolism is a complex disease resulting from the interaction of a multitude of both genetic and environmental factors that can affect the cascade of biochemical reactions involved. Single-nucleotide polymorphisms in the genes that code for coagulation factors V (factor V Leiden) and II (prothrombin G20210A), as well as the methylenetetrahydrofolate reductase (MTHFR C677T) gene, have been implicated in the majority of cases of hereditary thrombophilia. In this study the authors evaluated the coexistence of the MTHFR polymorphism in 96 patients with a clinical suspicion for thrombosis who also have either the factor V Leiden polymorphism or the prothrombin G20210A polymorphism. Results indicate that the frequency of the MTHFR polymorphism was similar between the study and control groups with respect to heterozygosity (36.5% vs. 55.3%) and homozygosity (20.8% vs. 14.9%). These data suggest that the MTHFR polymorphism is not associated preferentially with patients who have had or who are at risk of developing a thrombotic event. In this study, patients with the factor V Leiden polymorphism or the prothrombin G20210A polymorphism were considered to be at risk.
Diagn Mol Pathol 2001 Jun
PMID:Coexistence of the methylenetetrahydrofolate reductase single-nucleotide polymorphism (C677T) in patients with the factor V Leiden or prothrombin G20210A polymorphisms. 1138 20

Tryptophan hydroxylase (TPH; EC 1.14.16.4) catalyzes the first rate-limiting step of serotonin biosynthesis by converting l-tryptophan to 5-hydroxytryptophan. Serotonin controls multiple vegetative functions and modulates sensory and alpha-motor neurons at the spinal level. We report on five boys with floppiness in infancy followed by motor delay, development of a hypotonic-ataxic syndrome, learning disability, and short attention span. Cerebrospinal fluid (CSF) analysis showed a 51 to 65% reduction of the serotonin end-metabolite 5-hydroxyindoleacetic acid (5HIAA) compared to age-matched median values. In one out of five patients a low CSF 5-methyltetrahydrofolate (MTHF) was present probably due to the common C677T heterozygous mutation of the methylenetetrahydrofolate reductase (MTHFR) gene. Baseline 24-h urinary excretion showed diminished 5HIAA values, not changing after a single oral load with l-tryptophan (50-70 mg/kg), but normalizing after 5-hydroxytryptophan administration (1 mg/kg). Treatment with 5-hydroxytryptophan (4-6 mg/kg) and carbidopa (0.5-1.0 mg/kg) resulted in clinical amelioration and normalization of 5HIAA levels in CSF and urine. In the patient with additional MTHFR heterozygosity, a heterozygous missense mutation within exon 6 (G529A) of the TPH gene caused an exchange of valine by isoleucine at codon 177 (V177I). This has been interpreted as a rare DNA variant because the pedigree analysis did not provide any genotype-phenotype correlation. In the other four patients the TPH gene analysis was normal. In conclusion, this new neurodevelopmental syndrome responsive to treatment with 5-hydroxytryptophan and carbidopa might result from an overall reduced capacity of serotonin production due to a TPH gene regulatory defect, unknown factors inactivating the TPH enzyme, or selective loss of serotonergic neurons.
Mol Genet Metab 2001 Jun
PMID:A novel neurodevelopmental syndrome responsive to 5-hydroxytryptophan and carbidopa. 1138 54

Increased plasma concentrations of homocysteine have been found in patients with coronary artery disease (CAD) and essential hypertension (EH) and in patients with diabetic complications. The 677C/T methylenetetrahydrofolate reductase (MTHFR) gene polymorphism is related to the MTHFR enzyme activity and to the plasma homocysteine concentration. This study was designed to investigate an association of this polymorphism with CAD, EH, and type II diabetes mellitus in the Czech population. The MTHFR genotypes were assessed by the polymerase chain reaction-based methodology in a sample of 1199 unrelated Caucasian subjects with CAD, EH, type II diabetes, or a combination of these diseases, and in healthy subjects. Allele frequencies of the MTHFR polymorphism differed considerably between women with and without type II diabetes mellitus (P = 0.00069), with a higher frequency of the C allele in the diabetic women. In addition, the MTHFR T allele frequency was significantly higher in normotensive subjects with CAD compared with normotensive subjects without this disease (P = 0.020). Both associations were confirmed by multiple logistic regressions. In conclusion, while the C allele of the 677C/T MTHFR polymorphism is associated with type II diabetes mellitus in women, the T allele is associated with CAD only in normotensive subjects of Czech origin.
Mol Genet Metab 2001 Jun
PMID:Methylenetetrahydrofolate reductase polymorphism, type II diabetes mellitus, coronary artery disease, and essential hypertension in the Czech population. 1138 55

Hyperhomocysteinemia is known to be associated with an increased risk of myocardial infarction, stroke, peripheral arterial disease, and venous thrombosis. Gene polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS) may account for reduced enzyme activity and hyperhomocysteinemia. A recent study has documented evidence of polygenic regulation of plasma homocyteine. We report here on a case of occlusive stroke at young age and hyperhomocysteinemia with homozygous VN (677C to T) variant in the MTHFR gene as well as homozygous D/D (2756G to A) variant in the MS gene.
Exp Mol Med 2001 Jun 30
PMID:Homozygous VN (677C to T) and d/D (2756G to A) variants in the methylenetetrahydrofolate and methionine synthase genes in a case of hyperhomocysteinemia with stroke at young age. 1146 Aug 81

The effect of four polymorphic genes of folate-dependent methionine biosynthesis have been investigated in mothers affected by a neural tube defect pregnancy (NTD) and matched controls. The influence of the various genotypes on total red cell 5-methyl-H(4)folate,5,10-methenyl-H(4)folate, and 5-formyl-H(4)folate is reported, as is the effect on homocysteine and radioassay folate in both serum and red cells. All of the single nucleotide polymorphisms studied would seem to contribute to the cellular folate profile in some way. From the data presented, and from the work of others, it is likely that C677T 5,10-methylenetetrahydrofolate reductase is the most important of these polymorphisms. Control mother folate profiles seem reasonably predictive of any given methionine cycle mutation, but profiles in NTD mothers do not. On this basis, it seems likely that some other, as yet unidentified folate lesion is causal for NTD. In NTD-C677T 5,10-methylenetetrahydrofolate reductase in particular, indexes of folate depletion such as high-performance liquid chromatography (HPLC) folate level, oligo-gamma-glutamyl chain length, homocysteine, and radioassay folate values all seem to deteriorate with increased mutant allele carriage. This indicates that this folate polymorphism may provide a critical threshold effect that helps to promote NTD occurrence in the presence of another, as yet unidentified folate-related factor. In more general terms, on a by genotype basis, all 11 genotypes studied give NTD mothers a higher homocysteine compared to controls. Furthermore, a trend that is less universal indicates that NTD mothers have higher 5,10-methenyl-H(4)folate and 5-methyl-H(4)folate levels and lower 5-formyl-H(4)folate and H(4)PteGlu(1) levels than do controls. One of the most consistent, and possibly specific, differences between participant groups is a statistically significant elevation of 5,10-methenyl-H(4)folate in NTD mothers (affects three genotypes). Possible interpretations of this finding are discussed.
Mol Genet Metab 2001 Aug
PMID:An examination of polymorphic genes and folate metabolism in mothers affected by a spina bifida pregnancy. 1150 14

To investigate the prevalence of the C677T and A1298C single nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene in Caucasian and Hispanic populations, EDTA-anticoagulated whole blood specimens were collected from a total of 100 random patients, 50 Caucasians and 50 Hispanics of Puerto Rican dissent. The prevalence of the two MTHFR SNPs was determined by polymerase chain reaction (PCR) mediated restriction fragment length polymorphism analysis. In the Caucasian population, homozygosity for the MTHFR A1298C SNP was detected in 4% (2/50) of the individuals tested, while 42% (21/50) were heterozygous for this SNP. Among Hispanics, 4% (2/50) were homozygous and 38% (19/50) heterozygous for the A1298C SNP. Homozygosity for the C677T MTHFR SNP was detected in 16% (8/50) and 10% (5/50) of Caucasians and Hispanics, respectively. In this study, the frequency of the C677T heterozygotes was very high at 56% (28/50) and 52% (26/50) Caucasians and Hispanics, respectively. C677T and A1298C are common SNPs in the MTHFR gene. The high prevalence of these SNPs in both Caucasian and Hispanic populations demonstrates the possibility of compounding effects of these SNPs in the pathogenesis of human diseases. While subgroups of patients may exhibit some clinical phenotype linked to these SNPs, our analysis demonstrates the need for careful interpretation of SNP data in the context of population screening.
Int J Mol Med 2001 Nov
PMID:Single nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene are common in US Caucasian and Hispanic American populations. 1160 19

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.
J Mol Med (Berl) 2001 Sep
PMID:A second common variant in the methylenetetrahydrofolate reductase (MTHFR) gene and its relationship to MTHFR enzyme activity, homocysteine, and cardiovascular disease risk. 1169 65

Maternal mild hyperhomocysteinemia is associated with increased risk for bearing children with neural tube defects (NTD). Folate intake corrects hyperhomocysteinemia and prevents up to 70% of NTD. The curly-tail (ct) mouse, an animal model for NTD, has been suggested to display features that closely resemble the human defect. We therefore investigated folate metabolism in ct mice. On control and folate-/choline-deficient diets, ct mice exhibited higher plasma homocysteine levels than control C57Bl/6 mice. This increase was associated with increased liver S-Adenosylhomocysteine and decreased S-adenosylmethionine:S-adenosylhomocysteine (SAM/SAH) ratios. Since the ct locus maps in close proximity to the gene for methylenetetrahydrofolate reductase (Mthfr), a modifier of homocysteine levels in man, we also assayed Mthfr activity and sequenced the 5(') regulatory region; these experiments suggested that Mthfr is not defective in the ct strain. Finally, we examined the influence of dietary folate on NTD incidence in the ct strain, but did not identify significant differences among the four diets used in the study. Our work suggests that altered homocysteine metabolism may contribute to the pathogenetic mechanism of the ct defect, but, unlike human NTD, nutritional or genetic deficiencies in folate metabolism do not appear to play a significant direct role.
Mol Genet Metab 2002 Aug
PMID:The curly-tail (ct) mouse, an animal model of neural tube defects, displays altered homocysteine metabolism without folate responsiveness or a defect in Mthfr. 1220 34

Although controversial, diminished activity of 5,10 methylenetetrahydrofolate reductase (MTHFR), a regulatory enzyme of homocysteine metabolism, may predispose to migraine in Turkish people. In a case-control study, we determined the prevalence of two common MTHFR polymorphisms,C677T and A1298C, in 102 migraine patients (23 migraine with aura, 70 migraine without aura and nine with tension-type headache) and compared it to that of 136 healthy controls. The frequencies of the T allele of MTHFR677 and the C allele of MTHFR1298 were significantly higher in the total migraine population (33.82%, 33.82%) than in controls (25.38% and 24.26%), respectively. The genotypes T677T and C1298C were the only genotypes significantly associated with migraine (OR=5.702; 95% CI=1.184-27.457; P=0.015) and (OR=8.933; 95% CI=1.953-40.869; P=0.001), respectively). Individuals with migraine with aura with C1298C and C677C/C1298C genotypes were even more profoundly associated with migraine risk than others (OR=14.105; 95% CI=2.417-82.320; P=0.0001) and (OR=10.050; 95% CI=1.580-63.907; P=0.003), respectively. However individuals with migraine without aura with T677T and C1298C genotypes showed the same susceptibility (OR=7.444; 95% CI=1.503-36.863); P=0.005). Patients with C1298C and C677C/C1298C genotypes may also predispose to tension-type headache (OR=8.375; 95% CI=0.685-102.458); P=0.049).
Brain Res Mol Brain Res 2003 Mar 17
PMID:Association of the C677T and A1298C polymorphisms in the 5,10 methylenetetrahydrofolate reductase gene in patients with migraine risk. 1265 8

Methotrexate (MTX), widely used in the treatment of rheumatoid arthritis (RA), inhibits dihydrofolate reductase (DHFR) and folate-dependent enzymes. Thymidylate synthase (TS) and methylenetetrahydrofolate reductase (MTHFR) are key enzymes in the folate metabolism and both have been shown to be polymorphic affecting the enzyme activity. To clarify the association between these genetic variations and MTX-related toxicity and efficacy in the treatment of RA, a total of 167 Japanese individuals with RA, including 52 and 63 patients treated with low-dose MTX with or without adverse effects, respectively, and 52 patients without MTX administration were analyzed. Among the 93 patients treated with MTX for >2 months, significantly more patients homozygous for the triple-repeat allele of the polymorphism in the promoter region of the TYMS gene required higher dose of MTX compared to those having at least a double-repeat allele (P=0.033). The incidence of > or =50% improvement in the serum CRP level was significantly higher in patients homozygous for the deletion allele of the polymorphism in the 3'-untranslated region (UTR) of the TYMS gene (P=0.0383). The allele frequency of the insertion/deletion polymorphism in the TYMS 3'UTR in Japanese was significantly different from that in Caucasians (P<0.0001), as was the tandem-repeat polymorphism in its promoter region. On the other hand, MTHFR C677T and A1298C polymorphisms showed no association with MTX-related toxicity or efficacy. Our results suggest that the genotyping for the TYMS polymorphisms may become a useful indicator in determining the appropriate dose of MTX in patients with RA.
Int J Mol Med 2003 May
PMID:Polymorphisms in the thymidylate synthase and methylenetetrahydrofolate reductase genes and sensitivity to the low-dose methotrexate therapy in patients with rheumatoid arthritis. 1268 95


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