Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia.
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We previously reported that 2 polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene at positions C677T and A1298C were associated with lower risk of adult acute lymphocytic leukemia (ALL). In the present study, we have examined whether polymorphisms in other folate-metabolizing genes play a role in ALL susceptibility. Polymorphisms in methionine synthase (MS A2756G), cytosolic serine hydroxymethyltransferase (SHMT1 C1420T), and a double (2R2R) or triple (3R3R) 28-bp tandem repeat in the promoter region of thymidylate synthase (TS) were studied and found to modulate ALL risk. In a univariate analysis, SHMT1 1420CT individuals exhibited a 2.1-fold decrease in ALL risk (odds ratio [OR] = 0.48; 95% confidence interval [CI], 0.25-0.91), whereas the 1420TT genotype conferred a 3.3-fold reduction in risk (OR = 0.31; 95% CI, 0.10-0.90). Similarly, TS 2R3R individuals exhibited a 2.8-fold reduction in ALL risk (OR = 0.36; 95% CI: 0.16-0.83), while the TS 3R3R genotype conferred an even greater level of protection (OR = 0.25; 95% CI, 0.08-0.78). However, no significant associations were evident for the MS 2756AG polymorphism (OR = 0.79; 95% CI, 0.38-1.7). In addition, potential interactions between the SHMT1 and TS or MS genes were observed. TS 3R3R individuals who were SHMT1 1420CT/TT had a 13.9-fold decreased ALL risk (OR = 0.072; 95% CI, 0.0067-0.77). Further, MS 2756AG individuals who were SHMT1 1420CT/TT had a 5.6-fold reduction in ALL risk (OR = 0.18; 95% CI, 0.05-0.63). This study suggests an important role for uracil misincorporation and resultant chromosomal damage in the pathogenesis of ALL, and that genetic interactions involving low penetrance polymorphisms in folate-metabolizing genes may increase ALL risk. (+info)
Hyperhomocysteinemia due to methionine synthase deficiency, cblG: structure of the MTR gene, genotype diversity, and recognition of a common mutation, P1173L.
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Mutations in the MTR gene, which encodes methionine synthase on human chromosome 1p43, result in the methylcobalamin deficiency G (cblG) disorder, which is characterized by homocystinuria, hyperhomocysteinemia, and hypomethioninemia. To investigate the molecular basis of the disorder, we have characterized the structure of the MTR gene, thereby identifying exon-intron boundaries. This enabled amplification of each of the 33 exons of the gene, from genomic DNA from a panel of 21 patients with cblG. Thirteen novel mutations were identified. These included five deletions (c.12-13delGC, c.381delA, c.2101delT, c.2669-2670delTG, and c.2796-2800delAAGTC) and two nonsense mutations (R585X and E1204X) that would result in synthesis of truncated proteins that lack portions critical for enzyme function. One mutation was identified that resulted in conversion of A to C of the invariant A of the 3' splice site of intron 9. Five missense mutations (A410P, S437Y, S450H, H595P, and I804T) were identified. The latter mutations, as well as the splice-site mutation, were not detected in a panel of 50 anonymous DNA samples, suggesting that these sequence changes are not polymorphisms present in the general population. In addition, a previously described missense mutation, P1173L, was detected in 16 patients in an expanded panel of 24 patients with cblG. Analysis of haplotypes constructed using sequence polymorphisms identified within the MTR gene demonstrated that this mutation, a C-->T transition in a CpG island, has occurred on at least two separate genetic backgrounds. (+info)
Methionine synthase polymorphism A2756G is associated with susceptibility for thromboembolic events and altered B vitamin/thiol metabolism.
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BACKGROUND AND OBJECTIVES: Vitamin B12 dependent methionine synthase (MS) regulates de novo production of methionine from homocysteine (Hcy). Since moderate elevations in Hcy are considered vasculotoxic, we examined a common variant (A2756G-MS) of the gene coding for this enzyme as a risk for thromboembolism. DESIGN AND METHODS: We investigated A2756G-MS and folate/thiol status in 51 individuals who had experienced a thromboembolic event (TE) and 95 subjects being treated for non-thromboembolic (NTE) vascular problems. RESULTS: The prevalence of the mutant G allele was lower in TE subjects than in controls, indicating a protective role for this base substitution (OR 0.39; 95%CI 0.20-0.78; p=0.010). Consistent with an advantage conferred by this allele, heterozygotes had generally lower levels of Hcy and glutathione (GSH), and higher levels of B-vitamins than wildtypes. The OR for the wildtype having an increased risk for TE was 2.32 (95%CI 1.06-5.08). Additionally, as might be predicted, TE-wildtypes had elevated GSH levels compared to corresponding NTE-wildtypes (p=0.004) - a likely response to oxidative stress. NTE subjects showed a dramatic reduction in Hcy between wildtype and heterozygote (p=0.017), and again between recessive and heterozygote genotypes (p=0.002). The same pattern, although not significant, occurred in TE subjects. The similarity in Hcy between clinical groups for each genotype raises questions on the etiological role of Hcy in TE. The functional relationship between enzyme variant and its B12-cofactor may be of more interest, since the polymorphic site occurs near the B12-binding domain, and our results indicate wildtype-TE subjects have a much lower level of vitamin B12 than heterozygote-TE subjects (p=0.0019). This effect is attenuated in NTE subjects. INTERPRETATION AND CONCLUSIONS: . A2756G-MS may protect against a thromboembolic event. The role of Hcy remains unclear. (+info)
Methionine supply to growing steers affects hepatic activities of methionine synthase and betaine-homocysteine methyltransferase, but not cystathionine synthase.
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The effects of supplemental methionine (Met), supplied abomasally, on the activities of methionine synthase (MS), cystathionine synthase (CS) and betaine-homocysteine methyltransferase (BHMT) were studied in growing steers. Six Holstein steers (205 kg) were used in a replicated 3 x 3 Latin square experiment. Steers were fed 2.6 kg dry matter daily of a diet containing 83% soybean hulls and 8% wheat straw. Ruminal infusions of 180 g/d acetate, 180 g/d propionate, 45 g/d butyrate, and abomasal infusion of 300 g/d dextrose provided additional energy. An amino acid mixture (299 g/d) limiting in Met was infused into the abomasum to ensure that nonsulfur amino acids did not limit growth. Treatments were infused abomasally and included 0, 5 or 10 g/d L-Met. Retained N (20.5, 26.9 and 31.6 g/d for 0, 5 and 10 g/d L-Met, respectively) increased (P < 0.01) linearly with increased supplemental Met. Hepatic Met, vitamin B-12, S-adenosylmethionine and S-adenosylhomocysteine were not affected by Met supplementation. Hepatic folates tended (P = 0.07) to decrease linearly with Met supplementation. All three enzymes were detected in hepatic tissue of our steers. Hepatic CS activity was not affected by Met supplementation. Hepatic MS decreased (P < 0.01) linearly with increasing Met supply, and hepatic BHMT activity responded quadratically (P = 0.04), with 0 and 10 g/d Met being higher than the intermediate level. Data from this experiment indicate that sulfur amino acid metabolism may be regulated differently in cattle than in other tested species. (+info)
Nucleotide sequence diversity at the methionine synthase locus in endangered Dunnia sinensis (Rubiaceae): an evaluation of the positive selection hypothesis.
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Methionine synthase is a key enzyme for the synthesis of the aspartate-derived methionine, the immediate precursor of S-adenosyl-methionine, which has been illustrated to be associated with plant growth and pathogen interactions. In this study we tested the positive selection hypothesis of molecular evolution of the methionine synthase gene in Dunnia sinensis. In the entire sample of 87 sequences, 22 haplotypes of introns and 16 haplotypes of exons were identified. An excess of polymorphism over the neutral expectation for the class of unique nucleotide polymorphisms was observed in both exon and intron sequences. Ten replacement substitutions versus six synonymous substitutions among lineages, although nonsignificant, revealed that some advantageous mutants might have been favored. The distribution of d(N)/d(S) > 1 at nodes between closely related haplotypes in the gene network also indicated weak and variable positive selection. Nevertheless, low levels of genetic diversity in exons (theta; = 0.0052) and introns (theta; = 0.0070) of the methionine synthase gene of the outcrossing Dunnia were also attributed to the endangered status of the species. The atpB-rbcL intergenic spacer of cpDNA and the ribosomal internal transcribed spacer of mtDNA were used to discern the relative effectiveness of natural selection from intrinsic evolutionary forces. The low levels of nucleotide polymorphisms in both organelle spacers and the significant population differentiation reflected the effect of population-species history and demography. Two major lineages of the methionine synthase gene genealogy were recovered corresponding to two geographic regions, a result that was consistent with organelle phylogenies. Both past fragmentation and recent habitat disturbance causing complete bottlenecks may have resulted in population decline and geographic isolation and may have led to the depletion of genetic variation at loci in nuclear and organelle genomes. (+info)
Germ-line variants in methyl-group metabolism genes and susceptibility to DNA methylation in normal tissues and human primary tumors.
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Aberrant DNA methylation is recognized as being a common feature of human neoplasia.CpG island hypermethylation and global genomic hypomethylation occur simultaneously in the cancer cell. However, very little is known about the interindividual inherited susceptibility to these epigenetic processes. To address this matter, we have genotyped in 233 cancer patients (with colorectal, breast, or lung tumors), four germ-line variants in three key genes involved in the metabolism of the methyl group, methylene-tetrahydrofolate reductase, methionine synthase, and cystathionine beta-synthase, and analyzed their association with DNA methylation parameters. The epigenetic features analyzed were the 5-methylcytosine content in the genome of the tumors and their normal counterparts, and the presence of CpG island hypermethylation of tumor suppressor genes (p16(INK4a), p14(ARF), hMLH1, MGMT, APC, LKB1, DAPK, GSTP1, BRCA1, RAR beta 2, CDH1, and RASSF1). Two positive associations were found. First, carriers of genotypes containing the methylene-tetrahydrofolate reductase 677T allele show constitutive low levels of 5-methylcytosine in their genomes (P = 0.002), and tumors in these patients do not achieve severe degrees of global hypomethylation (P = 0.047). Second, tumors occurring in homozygous carriers of the methionine synthase 2756G allele show a lower number of hypermethylated CpG islands of tumor suppressor genes (P = 0.029). The existence of these associations may provide another example of the interplay between genetic and epigenetic factors in the cancer cell. (+info)
Acute valproate administration impairs methionine metabolism in rats.
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Valproate (VPA) is a drug widely used to treat epilepsy, but it has serious adverse effects including hepatotoxicity, teratogenicity and antifolate activity. The mechanism underlying VPA toxicity is unclear although an interaction with folate and other metabolites involved in methionine metabolism has been suggested. The present study was undertaken to evaluate potential changes in the metabolic function of the methionine cycle after acute exposure to a single dose of valproate. Female Wistar rats (n = 30) were treated with 400 mg/kg of VPA. Different groups of six rats were killed at 1 (t1), 3 (t3), 6 (t6), 9 (t9), and 24 (t24) hours after the injection. One group of rats was untreated (n = 6) and was considered the control group. The most pronounced effects of VPA administration were observed 1 h after drug injection. VPA induced a 56% reduction in methionine adenosyltransferase activity and a 54% reduction in plasma vitamin B-6. Increases in the hepatic concentration of S-adenosylhomocysteine and oxidized glutathione, and a reduction in the S-adenosylmethionine/S-adenosylhomocysteine transmethylation ratio also occurred at 1 h. All of these alterations, however, were normalized within 24 h, parallel with a decrease in serum VPA concentration. The acute effects of VPA suggest that the alterations in the methionine cycle could be the common mechanism underlying the hepatotoxic, teratogenic and antifolate effects of the drug. (+info)
Maternal genetic effects, exerted by genes involved in homocysteine remethylation, influence the risk of spina bifida.
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There is currently considerable interest in the relationship between variation in genes that are involved in the folate-homocysteine metabolic axis and the risk of spina bifida. The evaluation of this relationship is, however, complicated by the potential involvement of both the maternal and the embryonic genotype in determination of disease risk. The present study was designed to address questions regarding both maternal and embryonic genetic risk factors for spina bifida by use of the two-step transmission/disequilibrium test. Analysis of data on variants of two genes involved in homocysteine remethylation/methionine biosynthesis--methionine synthase (MTR) A2756G and methionine synthase reductase (MTRR) A66G--provided evidence that both variants influence the risk of spina bifida via the maternal rather than the embryonic genotype. For both variants, the risk of having a child with spina bifida appears to increase with the number of high-risk alleles in the maternal genotype: MTR (R1=2.16, 95% CI 0.92-5.06; R2=6.58, 95% CI 0.87-49.67) and MTRR (R1=2.05, 95% CI 1.05-3.99; R2=3.15, 95% CI 0.92-10.85). These findings highlight the importance of considering both the maternal and embryonic genotype when evaluating putative spina bifida susceptibility loci. (+info)