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NTD Risk (ntd + risk)
Selected AbstractsA common variant in MTHFD1L is associated with neural tube defects and mRNA splicing efficiency,HUMAN MUTATION, Issue 12 2009Anne Parle-McDermott Abstract Polymorphisms in folate-related genes have emerged as important risk factors in a range of diseases including neural tube defects (NTDs), cancer, and coronary artery disease (CAD). Having previously identified a polymorphism within the cytoplasmic folate enzyme, MTHFD1, as a maternal risk factor for NTDs, we considered the more recently identified mitochondrial paralogue, MTHFD1L, as a candidate gene for NTD association. We identified a common deletion/insertion polymorphism, rs3832406, c.781-6823ATT(7,9), which influences splicing efficiency and is strongly associated with NTD risk. Three alleles of rs3832406 were detected in the Irish population with varying numbers of ATT repeats: Allele 1 consists of ATT7, whereas Alleles 2 and 3 consist of ATT8 and ATT9, respectively. Allele 2 of this triallelic polymorphism showed a decreased case risk as demonstrated by case,control logistic regression (P=0.002) and by transmission disequilibrium test (TDT) (P=0.001), whereas Allele 1 showed an increased case risk. Allele 3 showed no influence on NTD risk and represents the lowest frequency allele (0.15). Additional single nucleotide polymorphism (SNP) genotyping in the same genomic region provides additional supportive evidence of an association. We demonstrate that two of the three alleles of rs3832406 are functionally different and influence the splicing efficiency of the alternate MTHFD1L mRNA transcripts. Hum Mutat 30:1,7, 2009. © 2009 Wiley-Liss, Inc. [source] The folate metabolic enzyme ALDH1L1 is restricted to the midline of the early CNS, suggesting a role in human neural tube defectsTHE JOURNAL OF COMPARATIVE NEUROLOGY, Issue 2 2007Todd E. Anthony Abstract Folate supplementation prevents up to 70% of human neural tube defects (NTDs), although the precise cellular and metabolic sites of action remain undefined. One possibility is that folate modulates the function of metabolic enzymes expressed in cellular populations involved in neural tube closure. Here we show that the folate metabolic enzyme ALDH1L1 is cell-specifically expressed in PAX3-negative radial glia at the midline of the neural tube during early murine embryogenesis. Midline restriction is not a general property of this branch of folate metabolism, as MTHFD1 displays broad and apparently ubiquitous expression throughout the neural tube. Consistent with previous work showing antiproliferative effects in vitro, ALDH1L1 upregulation during central nervous system (CNS) development correlates with reduced proliferation and most midline ALDH1L1+ cells are quiescent. These data provide the first evidence for localized differences in folate metabolism within the early neural tube and suggest that folate might modulate proliferation via effects on midline Aldh1l1+ cells. To begin addressing its role in neurulation, we analyzed a microdeletion mouse strain lacking Aldh1l1 and observed neither increased failure of neural tube closure nor detectable proliferation defects. Although these results indicate that loss-of-function Aldh1l1 mutations do not impair these processes in mice, the specific midline expression of ALDH1L1 and its ability to dominantly suppress proliferation in a folate responsive manner may suggest that mutations contributing to disease are gain-of-function, rather than loss-of-function. Moreover, a role for loss-of-function mutations in human NTDs remains possible, as Mthfr null mice do not develop NTDs even though MTHFR mutations increase human NTD risk. J. Comp. Neurol. 500:368,383, 2007. © 2006 Wiley-Liss, Inc. [source] Dietary methionine intake and neural tube defects in Mexican-American womenBIRTH DEFECTS RESEARCH, Issue 6 2010Anna Graham Abstract BACKGROUND Nutrients other than maternal folic acid are also thought to play a role in preventing neural tube defects (NTDs). Evidence suggests that methionine interacts with folic acid and vitamin B12 in the methylation of contractile proteins involved in closing the neural folds. The role of dietary intake of methionine in NTD risk has not been specifically studied among Mexican Americans, a population with one of the highest prevalences of NTDs in the United States. METHODS We conducted a case,control study of 184 Mexican American women with NTD-affected pregnancies (case women) and 225 women with normal offspring (control women) who resided along the Texas-Mexico border. The average daily intakes of methionine were calculated from periconceptional food frequency questionnaire data. Women were categorized according to quartiles of daily methionine intake, based on the control mothers' distribution, and the risk for an NTD-affected pregnancy was calculated using the lowest quartile of intake as the referent. RESULTS With adjustment for income, body mass index, hyperinsulinemia, and diarrhea, the odds ratios for increasing quartile of methionine intake were: 0.95 (95% confidence interval [CI], 0.48,1.90), 0.92 (95% CI, 0.46,1.84), and 0.66 (95% CI, 0.30,1.45). Some evidence of interaction between dietary methionine and serum vitamin B12 was noted particularly at higher levels of both components. CONCLUSIONS This study was limited by a small sample size but examined this association in an exclusively Hispanic population. Results were suggestive of a potential protective effect for NTDs with increasing maternal dietary methionine intake. Birth Defects Research (Part A), 2010. © 2010 Wiley-Liss, Inc. [source] Correlation of polymorphism of MTHFRs and RFC-1 genes with neural tube defects in ChinaBIRTH DEFECTS RESEARCH, Issue 1 2008Yali Shang Abstract BACKGROUND: Maternal periconceptional supplementation of folate reduces the incidence of neonatal Neural Tube Defects, indicating that changes in folate metabolism play a role in formation of NTDs. The mutations on two genes involved in folate metabolism, the C677 of the MTHFR gene and the RFC-1(A80G) gene are potential risk factors of NTDs. METHODS: In this study, we analyzed the genotypic distributions and allele frequencies of MTHFR C677T and RFC-1 A80G polymorphisms in DNA samples from mothers with at least one previous child with NTDs (the NTD group) and controls. RESULTS: Our results indicated that there was a significant difference in the genotype and allele frequencies of RFC-1 80A,G between the NTD group and controls (p = .008 and p = .017, respectively). There was, however, no significant difference in the genotype and allele frequencies of the MTHFR 677C,T polymorphism between the NTD group and controls. The NTD group was further separated into the upper and lower types by location of abnormalities. The frequency of RFC-1 80A/G and 80G/G was significantly higher in the upper group than the control (p = .009 and p = .005, respectively). The frequency of G-alleles was also significantly higher in the upper group than the control (OR 2.42; p = .006; 95% CI: 1.28,4.58). For the MTHFR C677 gene, the frequency of T-alleles was significantly lower in the lower defect type than the control group (OR 0.32; p = .027; 95% CI: 0.11,0.9). CONCLUSIONS: These results suggest that in the Shanxi population RFC-1 polymorphisms may play a role in NTD risk, whereas the impact of MTHFR C677T polymorphisms requires further clarification. Birth Defects Research (Part A) 2008. © 2007 Wiley-Liss, Inc. [source] | ||||||||||