Methionine Synthase: High-Resolution Mapping of the Human Gene and Evaluation as a Candidate Locus for Neural Tube Defects

Brody, Lawrence C.; Baker, Priscilla J.; Chines, Peter S.; Musick, Anjene; Molloy, Anne M.; Swanson, Deborah A.; Kirke, Peadar N.; Ghosh, Soumitra; Scott, John M.; Mills, James L.

doi:10.1006/mgme.1999.2881

Cited by 27 publications

(22 citation statements)

References 44 publications

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Section: Discussionmentioning

confidence: 99%

“…This gene (MTR) encodes methionine synthase, which catalyzes the remethylation of homocysteine to methionine. Several studies have assessed the relationship between neural tube defects and variants of MTR, with conflicting results (e.g., Brody et al, 1999;De Marco et al, 2002;Johanning et al, 2000;Shaw et al, 1999;Doolin et al, 2002;Wilson et al, 1999;Zhu et al, 2003).The results of the analyses summarized in this paper should be interpreted with caution, given the number of comparisons that were performed and the relatively small numbers on which many of the comparisons are based. It is possible that the associations that were detected in our subjects may represent false-positive findings.…”

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confidence: 91%

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Evaluation of Potential Modifiers of the Palatal Phenotype in the 22q11.2 Deletion Syndrome

Driscoll

Boland

Emanuel

et al. 2006

Cleft Palate-Craniofac J

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Objective-To evaluate potential modifiers of the palatal phenotype in individuals with the 22q11.2 deletion syndrome.Design-Data from 356 subjects enrolled in a study of the 22q11.2 deletion syndrome were used to evaluate potential modifiers of the palatal phenotype. Specifically, subjects with and without velopharyngeal inadequacy and/or structural malformations of the palate were compared with respect to gender, race, and genotype for variants of seven genes that may influence palatal development.Methods-The chi-square test or Fisher exact test was used to evaluate the association between palatal phenotype and each potential modifier. Odds ratios and their associated 95% confidence intervals were used to measure the magnitude of the association between palatal phenotype, subject gender and race, and each of the bi-allelic variants.Results-The palatal phenotype observed in individuals with the 22q11.2 deletion syndrome was significantly associated with both gender and race. In addition, there was tentative evidence that the palatal phenotype may be influenced by variation within the gene that encodes methionine synthase.Conclusions-Variation in the palatal phenotype observed between individuals with the 22q11.2 deletion syndrome may be related to personal characteristics such as gender and race as well as variation within genes that reside outside of the 22q11.2 region. Keywords chromosome 22q11.2 deletion; genes; genotype; palate; penetrance; phenotype Hemizygous deletion of the chromosome 22q11.2 region results in a syndromic phenotype that encompasses the DiGeorge, velocardiofacial, and conotruncal anomaly face syndromes. Population-based estimates of the prevalence of this deletion range from 1 in 4500 to 1 in 7100 births (Botto et al., 2003;Tezenas du Montcel et al., 1996;Oskarsdottir et al., 2004), making it the most frequent known interstitial deletion in humans. The majority of individuals with the 22q11.2 deletion syndrome have a de novo three-megabase deletion. However, approximately 10% of patients with the 22q11.2 deletion syndrome have an inherited deletion, and approximately 10% have a smaller deletion (1.5 Mb) (Saitta et al., 2004;Yamagishi and Srivastava, 2003).The phenotypic consequences of hemizygous deletion of chromosome 22q11.2 are remarkably variable and can include cardiac, thymic, parathyroid, craniofacial, developmental, neurologic, and behavioral manifestations. None of these features appears to be fully penetrant, and each exhibits variable expressivity. For example, approximately 75% of patients with the 22q11.2 deletion syndrome have a cardiac defect, and a range of malformations (e.g., tetralogy of Fallot, interrupted aortic arch, septal defects) is observed among those who have such a defect (McDonald-McGinn et al., 1997;Ryan et al., 1997).The variability in the 22q11.2 deletion syndrome phenotype is largely unexplained. Variability is observed across unrelated patients and between affected family members who have presumably inherited identical deletions (Desmaze et al., 1993;McLe...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 91%

Evaluation of Potential Modifiers of the Palatal Phenotype in the 22q11.2 Deletion Syndrome

Driscoll

Boland

Emanuel

et al. 2006

Cleft Palate-Craniofac J

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“…[12] Also, it produces about 1265 amino acid residues and weighs 140.5 kDa. [3] Methionine synthase is a cytoplasmic enzyme that requires methylcobalamin for activity and catalyzes the remethylation of homocysteine to methionine.…”

Section: Introductionmentioning

confidence: 99%

Methionine synthase polymorphisms (MTR 2756 A>G and MTR 2758 C>G) frequencies and distribution in the Jordanian population and their correlation with neural tube defects in the population of the northern part of Jordan

Farra¹

2010

Indian J Hum Genet

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BACKGROUND:The human methionine synthase gene (MTR) is located on chromosome 1q43; it is of 105.24 kb and is made up of 33 exons. Methionine synthase is a cytoplasmic enzyme that requires methylcobalamin for activity and catalyzes the remethylation of homocysteine to methionine. In this reaction, the methyl group of 5-methyltetrahydrofolate is transferred to the enzyme bond cob(I) alamin to generate methylcobalamin, followed by the transfer of the methyl group to homocysteine to reform methionine.MATERIALS AND METHODS:The frequencies of the polymorphisms of MTR 2756A>G and MTR 2758C>G have been determined in this study in a sample of 491 individuals collected from all regions of Jordan and representing the Jordanian population. The different alleles and genotypes at the two polymorphic sites were identified using the Polymerase Chain Reaction - Restriction Fragment Length Polymorphism (PCR-RFLP) analysis.RESULTS:Showed that the percentages of the polymorphic alleles at the MTR 2756 position in the north, middle and south regions were 90.38, 92.65 and 83.69%, respectively, for the MTR 2756A allele, and were 9.61, 7.34 and 16.30%, respectively, for the MTR 2756G allele, with overall percentages in the whole Jordanian population of 90.73 and 9.27% for the MTR 2756A and MTR 2756G alleles, respectively. The percentages of the genotype MTR 2756AA were 82.90% in the northern region, 86.72% in the middle region and 71.73% in the southern region, and an overall percentage of MTR 2756AA in the whole Jordanian population was 83.50%. The frequencies of MTR 2756AG genotype in the northern, middle and southern regions were 14.95, 11.84 and 23.91%, respectively, with an overall percentage of 14.46% in the whole Jordanian population. The percentages of the genotype MTR 2756GG in the northern, middle and southern regions were 2.13, 1.42 and 4.34%, respectively, with an overall percentage of 2.04% in the whole Jordanian population. Only the wild type allele (C) of the MTR 2758C>G polymorphism was detected in this study. In addition, the association of MTR 2756A>G and MTR 2758C>G polymorphisms with the development of neural tube defects (NTDs) was examined using 17 cases of mothers from the northern part of Jordan, who gave birth to NTD affected children during the period of this study. Results showed no association between these two examined polymorphisms and the increase in maternal risk for giving birth to NTD children.CONCLUSION:results of this study recommend that examination should be done on larger populations to arrive at better conclusions. Also, more studies on gene–gene interaction should be done to examine the associations with NTDs.

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“…It is probably not surprising that the outcomes of these efforts have been inconsistent, because of the underlying low penetrance of the genetic effects, differences in population genetic and environmental susceptibility, low sample size, and often poorly matched controls in study design (Mitchell et al, 2004). In the large, ethnically homogeneous Irish cohort described previously, no important risk polymorphisms were identified in the gene encoding the most plausible biologic candidate, methionine synthase, or in its activating enzyme, methionine synthase reductase (Brody et al, 1999; O’Leary et al, 2005b). In addition, none were identified in the genes encoding the human folate receptor β gene (O’Leary et al, 2003), the reduced folate carrier, (O’Leary et al, 2006), cystathionine β-synthase (Ramsbottom et al, 1997), methylmalonyl CoA mutase (Parle-McDermott et al, 2003a), transcobalamin II (Swanson et al, 2005), or dihydrofolate reductase (Parle-McDermott et al, 2007).…”

Section: After Mthfr: Candidate Snps In Folate Linked Genes Become a mentioning

confidence: 96%

The search for genetic polymorphisms in the homocysteine/folate pathway that contribute to the etiology of human neural tube defects

Molloy

Brody

Mills

et al. 2009

Birth Defects Research

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In this paper, we trace the history of current research into the genetic and biochemical mechanisms that underlie folate-preventable neural tube defects (NTDs). The inspired suggestion by Smithells that common vitamins might prevent NTDs ignited a decade of biochemical investigations—first exploring the nutritional and metabolic factors related to NTDs, then onto the hunt for NTD genes. Although NTDs were known to have a strong genetic component, the concept of common genetic variance being linked to disease risk was relatively novel in 1995, when the first folate-related polymorphism associated with NTDs was discovered. The realization that more genes must be involved started a rush to find polymorphic needles in genetic haystacks. Early efforts entailed the intellectually challenging and time-consuming task of identifying and analyzing candidate single nucleotide polymorphisms (SNPs) in folate pathway genes. Luckily, human genome research has developed rapidly, and the search for the genetic factors that contribute to the etiology of human NTDs has evolved to mirror the increased level of knowledge and data available on the human genome. Large-scale candidate gene analysis and genome-wide association studies are now readily available. With the technical hurdles removed, the remaining challenge is to gather a sample large enough to uncover the polymorphisms that contribute to NTD risk. In some respects the real work is beginning. Although moving forward is exciting, it is humbling that the most important result—prevention of NTDs by maternal folic acid supplementation—was achieved years ago, the direct result of Smithells’ groundbreaking studies.

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Methionine Synthase: High-Resolution Mapping of the Human Gene and Evaluation as a Candidate Locus for Neural Tube Defects

Cited by 27 publications

References 44 publications

Evaluation of Potential Modifiers of the Palatal Phenotype in the 22q11.2 Deletion Syndrome

Evaluation of Potential Modifiers of the Palatal Phenotype in the 22q11.2 Deletion Syndrome

Methionine synthase polymorphisms (MTR 2756 A>G and MTR 2758 C>G) frequencies and distribution in the Jordanian population and their correlation with neural tube defects in the population of the northern part of Jordan

The search for genetic polymorphisms in the homocysteine/folate pathway that contribute to the etiology of human neural tube defects

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