Polymorphisms of 5,10-Methylenetetrahydrofolate Reductase and Cystathionine β-Synthase Genes as a Risk Factor for Neural Tube Defects in Sétif, Algeria

Houcher, Bakhouche; Bourouba, Romyla; Djabi, Farida; Yılmaz, Erkan; Eğin, Yonca; Akar, Nejat

doi:10.1159/000283086

Cited by 15 publications

(9 citation statements)

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“…Mutations of the CBS gene, such as the 844ins68 allele, have been described (Sebastio et al, 1995). There have been conflicting studies regarding the potential interaction among alleles of different folate-related genes, such as the 677C-T allele of the methylene tetrahydrofolate reductase ( MTHFR ) gene and the 844ins68 allele of CBS , and their combined contribution to risk of SB (Ramsbottom et al, 1997; Speer et al, 1999; de Franchis et al, 2002; Houcher et al, 2009). …”

Section: Introductionmentioning

confidence: 99%

Genetic studies of the cystathionine beta‐synthase gene and myelomeningocele

Tilley¹,

Au²

2011

Birth Defects Research

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BACKGROUND Among infants born with spina bifida, the most common defect is myelomeningocele (MM). The prevention of MM by maternal periconceptual folic acid (FA) supplementation has been extensively studied. The protective effect provided by FA suggests that the genes involved in folate metabolism, such as cystathionine beta-synthase (CBS), warrant further investigation. METHODS This study sequenced the DNA from 96 patients with MM to identify novel potential disease causing variants across the 17 exons of the CBS gene. The frequencies of known SNPs were identified and sequences that differed from the reference sequences were considered novel variants. Statistical analysis was performed using 2-sided Fisher's exact test to compare frequencies of SNPs between groups of patients and the known population frequencies. RESULTS We found a new variant in Exon 3 in one patient that result in a G/A change subsequently encoding a stop codon. Additionally, we found a new variant in the 3′-UTR of exon 17. Allele frequencies for ten known SNPs were determined: rs234706, rs72058776, rs1801181, rs6582281, rs71872941, rs12613, rs706208, rs706209, rs73906420, and rs9982921. Of the remaining 48 known SNPs, all tested DNAs were homozygous for the major allele. CONCLUSION We identified a previously undescribed variant in Exon 3 that encodes a stop codon, thus halting downstream translation of the CBS protein. According to the Human Splice Finder, the 3′-UTR variant found in Exon 17 is predicted to abolish the recognition sites for two splice binding factors, SRp40 and SF2/ASF. The functional significance of the 3′-UTR mutation needs to be investigated.

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Section: Introductionmentioning

confidence: 99%

Genetic studies of the cystathionine beta‐synthase gene and myelomeningocele

Tilley¹,

Au²

2011

Birth Defects Research

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“…Although this is not statistically significant the P-value is close to 0.05. The and the Need for Proper Periconceptional Folate Supplementation 208 same study also found an increased risk of NTDs in the elevated homocysteine mothers (24%) versus control (4.9%, P = 0.046) [38]. These observations therefore support the hypothesis that elevated homocysteine levels are commonly found in mothers with MTHFR 677TT genotype, which indicates an increased risk of having a child with a NTD.…”

Section: Neural Tube Defectsmentioning

confidence: 61%

“…A case control study in Setif, Algeria found higher homocysteine levels in MTHFR 677TT homozygous mothers with spina bifida children than in mothers of healthy children (P = 0.06) [38]. Although this is not statistically significant the P-value is close to 0.05.…”

Section: Neural Tube Defectsmentioning

confidence: 86%

“…Several studies have found positive association between the common MTHFR gene C677T polymorphism and risk of NTDs. The MTHFR gene 677TT genotype has been associated with a 4-fold increase risk of having a child with a NTD [38]. Interestingly, to date there are few studies that have extensively investigated the association between A1298C polymorphism and NTDs [39].…”

Section: Neural Tube Defectsmentioning

confidence: 99%

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Women with Methylenetetrahydrofolate Reductase Gene Polymorphism and the Need for Proper Periconceptional Folate Supplementation

Sullivan¹,

Murray²,

Assefa³

2015

JPP

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Maternal folate supplementation is critical for fetal development. Women with MTHFR (methylenetetrahydrofolate reductase) gene polymorphisms may not be getting the proper folate form to support fetal development. The objectives of this review were to: (1) undertake a comprehensive review on the association of MTHFR polymorphisms with the risk for various congenital diseases and other adverse pregnancy outcomes, (2) assess the efficacy and safety of current folic acid and other supplementations in women with the MTHFR polymorphism, and (3) provide guidance on the appropriate supplementation for women of childbearing potential with the MTHFR gene polymorphism in order to decrease these adverse pregnancy outcomes. Our assessments show that women with MTHFR gene polymorphism cannot efficiently convert folic acid to L-5-methyl-tetrahydofolate, the predominant active form of folic acid, due to reduced MTHFR enzymatic activity. L-5-methyl-tetrahydrofolate is currently commercially available under several brand names. Based on our comprehensive review and knowledge of the biochemistry of the folates, we recommend that L-5-methyltetrahydrofolate be given in combination with folic acid to women with MTHFR polymorphism that are pregnant or planning to become pregnant. Further study is needed to determine the optimal dose.

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“…Due to the declining prevalence of NTD in women taking folate supplements, genes in the folate metabolic pathway have been a prime target of investigations. The paper by Houcher et al [1] investigates whether common allelic variants of 5,10-methylenetetrahydrofolate reductase and cystathionine ␤ -synthase are causative of NTD in Algeria. These types of studies have been per-in the folate metabolic pathways will not reveal an underlying genetic cause of NTD [3] .…”

mentioning

confidence: 99%