Methionine synthase A2756G and reduced folate carrier1 A80G gene polymorphisms as maternal risk factors for Down syndrome in Egypt

Moustafa, Maha; Gaber, Elham; Fath, Gamal Abo El

doi:10.1016/j.ejmhg.2015.09.003

Cited by 5 publications

(4 citation statements)

References 26 publications

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“…Moustafa et al . [ 24 ] observed that mothers with MTR 2756 G genotype could be considered at risk for DS in Egyptians.…”

Section: Discussionmentioning

confidence: 99%

Role of folate metabolizing genes and homocysteine in mothers of Down syndrome children

Kaur¹,

Kaur²

2022

Tzu Chi Medical Journal

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Objectives: Folates are essential nutrients required for the synthesis of DNA/RNA in cell division and segregation. Folates are reduced and methylated in the liver with the help of enzymes such as methylenetetrahydrofolate reductase (MTHFR), MTR MTRR, reduced folate carrier 1, and cystathionine-β-synthase. Variants in the genes encoding these enzymes may lead to hypomethylation, resulting in nondisjunction which in turn increases the risk for Down syndrome (DS). The present study was conducted to genotype these genes and to see their association with homocysteine levels. Materials and Methods: A total of 213 mothers having DS children and 220 mothers having normal children were enrolled in the study. Genomic DNA was isolated from lymphocytes followed by polymerase chain reaction/Restriction Fragment Length Polymorphism for genotyping. Homocysteine levels were checked by chemoassay utilizing coumarin-based fluorescent probe. Results: Genotypic frequency of MTHFR 1298 A > C polymorphism was significantly different among cases and controls ( χ 2 = 5.83, P = 0.01), presence of C instead of A allele provided protection against DS in mothers (odds ratios = 0.57, 95% confidence interval = 0.35–0.91, P = 0.01). Higher levels of homocysteine were independently associated with the risk of having DS child ( P = 0.0001). Conclusion: Homocysteine acted as an independent risk factor in the present study and was not associated with folate metabolizing gene variants.

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“…Moustafa et al . [ 24 ] observed that mothers with MTR 2756 G genotype could be considered at risk for DS in Egyptians.…”

Section: Discussionmentioning

confidence: 99%

Role of folate metabolizing genes and homocysteine in mothers of Down syndrome children

Kaur¹,

Kaur²

2022

Tzu Chi Medical Journal

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“…We analysed maternal genotypes of selective mutant variants of the folate metabolic regulator genes, namely MTR A2756G, MTRR A66G, and MTHFR C677T & MTHFR A1298C. These variants were reported to be associated with DS birth in different ethnic populations [28][29][30] . We tested association of all four variants and obtained significant elevated odds in favour of the MII error group over the MI error group for homozygous minor and heterozygous genotypes of all four polymorphic sites except the 'GG' of MTR A2756G (Table 2).…”

Section: Discussionmentioning

confidence: 99%

Understanding etiology of chromosome 21 nondisjunction from gene × environment models

Halder

Pal

Ganguly

et al. 2021

Sci Rep

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Maternal risk factors and their interactions with each other that associate chromosome 21 nondisjunction are intriguing and need incisive study to be resolved. We determined recombination profile of nondisjoined chromosome 21 and maternal genotypes for four selected polymorphic variants from the folate regulators genes stratifying the women according to the origin of segregation error and age at conception. We conducted association study for genotype and maternal addiction to smokeless chewing tobacco, usually chopped tobacco leaves or paste of tobacco leaves with the incidence of Down syndrome birth. Additionally, we designed various logistic regression models to explore the effects of maternal genotype, maternal habit of smokeless chewing tobacco, maternal age at conception and all possible interactions among them on chromosome 21 nondisjunction. We found folate regulator gene mutations are associated with maternal meiosis II error. Regression models revealed smokeless chewing tobacco and folate polymorphic/mutant risk genotype interact with each other to increase the risk of reduced and single peri-centromeric recombination events on chromosome 21 that nondisjoined at meiosis II in the oocytes and the effect is maternal age independent. We inferred maternal folate polymorphic/mutant risk genotypes and habit of smokeless chewing tobacco interact with each other and increase the risk of meiosis II error in oocytes in maternal age-independent manner.

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“…The one SNP i.e. D919G (MTR c.2756A>G) has been extensively studied (Brandalize et al 2010;Zampieri et al 2012;Coppedè et al 2013;Victorino et al 2014;Li et al 2015;Sukla et al 2015;Moustafa et al 2016;Desai and Chauhan 2017b). However, the results were contradictory in different studies.…”

Section: Discussionmentioning

confidence: 99%

Predicting the functional and structural consequences of nsSNPs in human methionine synthase gene using computational tools

Desai¹,

Chauhan²

2019

Systems Biology in Reproductive Medicine

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Methionine synthase encoded by the MTR gene is one of the key enzymes involved in the SAM (S-Adenosyl Methionine) cycle catalyzing the conversion of homocysteine to methionine. Methionine plays an important role in the DNA, RNA, protein, phospholipids, and neurotransmitters methylation. It also maintains serum homocysteine level and indirectly regulates de novo nucleotide synthesis and repair. The current study predicted the functional consequences of nsSNPs in human MTR gene using SIFT, PolyPhen2, PROVEAN, SNAP2, PMut, nsSNPAnalyzer, PhD-SNP, SNPs&GO, I-Mutant, MuPro, and iPTREE-STAB. The PTM sites within the protein were predicted using ModPred and the phylogenetic conservations of amino acids & conserved domains of protein were predicted using ConSurf and NCBI conserved domain search tool respectively. The protein 3D structure was generated using SPARKS-X and analyzed using RAMPAGE. Structural deviation was analyzed using TM-Score. STRING analysis was preformed to predict protein-protein interactions. D621G, G682D, V744L, V766E, and R1027W were predicted to be the most deleterious nsSNPs in MTR. R1027 was predicted to having the three PTM sites and G682 & V744 were predicted as highly conserved residues. D621G, G682D, V744L, V776E, and R1027W were predicted to be within conserved domains of methionine synthase. The G682D, V744L, V776E, and R1027W were predicted to alter protein 3D structure. STRING predicted that methionine synthase interacting with 10 different proteins. The present study predicted D621G, G682D, V744L, V766E, and R1027W as functionally and structurally significant nsSNPs in human MTR gene. The present study can provide the significant information for further experimental analysis.

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Methionine synthase A2756G and reduced folate carrier1 A80G gene polymorphisms as maternal risk factors for Down syndrome in Egypt

Cited by 5 publications

References 26 publications

Role of folate metabolizing genes and homocysteine in mothers of Down syndrome children

Role of folate metabolizing genes and homocysteine in mothers of Down syndrome children

Understanding etiology of chromosome 21 nondisjunction from gene × environment models

Predicting the functional and structural consequences of nsSNPs in human methionine synthase gene using computational tools

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