Methionine synthase reductase (EC 126.96.36.199) is a flavoprotein essential for maintenance of methionine synthase in an active state. We characterized the human gene for methionine synthase reductase (MTRR). The gene is approximately 34kb and comprises 15 exons, varying in size from 43 to 1213bp, and 14 introns whose sizes vary from 108bp to 5kb. The positions of several junctions are conserved between the MTRR gene and the C. elegans ortholog, as well as with the rat cytochrome P450 reductase gene. A 1.3kb CpG island encompasses the 5'-flanking region and exon 1 and extends into intron 1. A short region including the transcription start site is sufficient to confer promoter activity, with a better outcome when accompanied by intron 1. The promoter region contains putative binding sites for Sp1, AP-1, AP-2 as well as CAAT motifs, but no consensus TATA box. Primer extension analysis revealed a single major transcription start site, located 137bp upstream of the previously reported initiator ATG. An alternative splicing event involving a portion of exon 1 predicts that translation can potentially be initiated at two different ATG codons. The gene was physically assigned to a narrow area between markers WI1755 and D5S1957.
"The MTRR gene is located on chromosome 5 at 5p15.3-p15.2 (Leclerc et al., 1999). A common variant has been identified within the flavin mononucleotide-binding domain of the MTRR gene, the A66G polymorphism (rs1801394), which results in an isoleucine-to-methionine (I22M) substitution and appears to interact less effectively with methionine synthase (Olteanu and Banerjee, 2001). "
[Show abstract][Hide abstract] ABSTRACT: Congenital heart defects (CHDs) are the most common birth defects; genes involved in homocysteine/folate metabolism may play important roles in CHDs. Methionine synthase reductase (MTRR) is one of the key regulatory enzymes involved in the metabolic pathway of homocysteine. We investigated whether two polymorphisms (A66G and C524T) of the MTRR gene are associated with CHDs. A total of 599 children with CHDs and 672 healthy children were included; the polymorphisms were detected by PCR and RFLP analysis. Significant differences in the distributions of A66G and C524T alleles were observed between CHD cases and controls, and slightly increased risks of CHD were associated with 66GG and 524CT genotypes (odds ratios = 1.545 and 1.419, respectively). The genotype frequencies of 524CT in the VSD subgroup, 66GG and 524CT in the PDA subgroup were significantly different from those of controls. In addition, the combined 66AA/524CT, 66AG/524CT and 66GG/524CT in CHDs had odds ratios = 1.589, 1.422 and 1.934, respectively. Increased risks were also observed in 66AA/524CT and 66GG/524CT for ASD, 66AG/524CT for VSD, as well as 66GG/524CT for PDA. In conclusion, MTRR A66G and C524T polymorphisms are associated with increased risk of CHDs.
"The gene was mapped to human chromosome 5p15.3–p15.2 [Leclerc et al., 1999], is 34-kb long, comprises 15 exons, and is thought to produce cytosolic and mitochondrial mRNA isoforms. So far, 15 pathogenic mutations in the MTRR gene have been reported in 13 cblE patients [Leclerc et al., 1998; Wilson et al., 1999a; Zavadakova et al., 2002; Vilaseca et al., 2003]. "
[Show abstract][Hide abstract] ABSTRACT: The cblE type of homocystinuria is a rare autosomal recessive disorder caused by impaired reductive activation of methionine synthase. Although earlier biochemical studies proposed that the methionine synthase enzyme might be activated by two different reducing systems, mutations were reported in only the methionine synthase reductase gene (MTRR) in cblE patients. The pathogenicity of MTRR mutations, however, has not yet been tested functionally. We report on nine patients of European origin affected by the cblE type of homocystinuria. They presented between 2 weeks and 3 years of age (median age 4 weeks) with anemia, which was macrocytic in only three patients, and with neurological involvement in all but two cases. Bone marrow examination performed in seven patients showed megaloblastic changes in all but one of them. All patients exhibited moderate to severe hyperhomocysteinemia (median plasma total homocysteine [Hcy] 92 mumol/L, range 44-169), while clearly reduced methionine was observed only in four cases. Pathogenic mutations were identified in both parental alleles of the MTRR gene in all patients. Five known (c.903+469T>C, c.1361C>T, c.1459G>A, c.1557-4_1557+3del7, and c.1622_1623dupTA) and three novel mutations (c.7A>T, c.1573C>T, and c.1953-6_1953-2del5) were detected. Importantly, transfection of fibroblasts of cblE patients with a wild-type MTRR minigene expression construct resulted in a significant approximately four-fold increase of methionine synthesis, indicating correction of the enzyme defect. Our study shows a link between a milder predominantly hematological presentation and homozygosity for the c.1361C>T mutation, but no other obvious genotype-phenotype correlation. The identification of mutations in the MTRR gene, together with restoration of methionine synthesis following MTRR minigene expression in cblE cells confirms that this disease is caused by defects in the MTRR gene.
Human Mutation 03/2005; 25(3):239-47. DOI:10.1002/humu.20131 · 5.14 Impact Factor
"Recent studies show that inadequate folate and/or vitamin B 12 status or MS inhibition, could results in lower rates of SAM synthesis and hence impaired SAM-dependent methylation reactions with a consequent elevation in the plasma level of HCY      . "
[Show abstract][Hide abstract] ABSTRACT: This study is directed towards investigating the ability of various forms of vitamin B12 to augment intracellular gluthathione (GSH) level as well as studying their possible protective effect against the thimerosal-inuced oxidative stress. SH-SY5Y human neuroblastoma cell culture system was used as a model for this study. Cells were acutely (60 minutes) treated with 3 different vitamin B12 derivatives (methyl-, hydroxy- and cyanocobalamin) in the presence and absence of thimerosal, vaccine antimicrobial agent. The results revealed that only methylcobalamin augmented the GSH level, as compared to other forms (hydrorxy- and cyanocobalamin). Also methylcobalamin was the only derivative that showed a protective effect against the thimerosal-induced depletion of GSH. Our findings provide evidence that thimerosal induces oxidative stress in human neuronal cells by depleting GSH and only methylcobalamin protects the cells against such insult and therfore improving the antioxidant intracellular capacity against oxidative stress, a common cause for the pathogenesis of many diseases including, autism.
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