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Key apoptotic genes APAF1 and CASP9 implicated in recurrent folate-resistant neural tube defects.

ABSTRACT: Neural tube defects (NTDs) remain one of the most serious birth defects, and although genes in several pathways have been implicated as risk factors for neural tube defects via knockout mouse models, very few molecular causes in humans have been identified. Whole exome sequencing identified deleterious variants in key apoptotic genes in two families with recurrent neural tube defects. Functional studies in fibroblasts indicate that these variants are loss-of-function, as apoptosis is significantly reduced. This is the first report of variants in apoptotic genes contributing to neural tube defect risk in humans.

SUBMITTER: Spellicy CJ

PROVIDER: S-EPMC5838979 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Key apoptotic genes APAF1 and CASP9 implicated in recurrent folate-resistant neural tube defects.

Spellicy Catherine J CJ Norris Joy J Bend Renee R Bupp Caleb C Mester Paul P Reynolds Tracy T Dean Jane J Peng Yunhui Y Alexov Emil E Schwartz Charles E CE Stevenson Roger S RS J Friez Michael M

European journal of human genetics : EJHG 20180122 3

Neural tube defects (NTDs) remain one of the most serious birth defects, and although genes in several pathways have been implicated as risk factors for neural tube defects via knockout mouse models, very few molecular causes in humans have been identified. Whole exome sequencing identified deleterious variants in key apoptotic genes in two families with recurrent neural tube defects. Functional studies in fibroblasts indicate that these variants are loss-of-function, as apoptosis is significant ...[more]

PMID: 29358613

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Project description:Periconceptional folic acid use can often prevent neural tube defects (NTDs). Variants of genes involved in folate metabolism in mothers and children have been associated with occurrence of NTDs. We identified Irish families with individuals affected by neural tube defects. In these families, we observed that neural tube defects and birth defects overall occurred at a higher rate in the maternal lineage compared with the paternal lineage. The goal of this study was to look for evidence for genetic effects that could explain the discrepancy in the occurrence of these birth defects in the maternal vs. paternal lineage. We genotyped blood samples from 322 individuals from NTD-affected Irish families, identified through their membership in spina bifida associations. We looked for differences in distribution in maternal vs. paternal lineages of five genetic polymorphisms: the DHFR 19 bp deletion, MTHFD1 1958G>A, MTHFR 1298A>C, MTHFR 677C>T, and SLC19A1 80A>G. In addition to looking at genotypes individually, we determined the number of genotypes associated with decreased folate metabolism in each relative ("risk genotypes") and compared the distribution of these genotypes in maternal vs. paternal relatives. Overall, maternal relatives had a higher number of genotypes associated with lower folate metabolism than paternal relatives (p = 0.017). We expected that relatives would share the same risk genotype as the individuals with NTDs and/or their mothers. However, we observed that maternal relatives had an over-abundance of any risk genotype, rather than one specific genotype. The observed genetic effects suggest an epigenetic mechanism in which decreased folate metabolism results in epigenetic alterations related to the increased rate of NTDs and other birth defects seen in the maternal lineage. Future studies on the etiology of NTDs and other birth defects could benefit from including multigenerational extended families, in order to explore potential epigenetic mechanisms.

Project description:ObjectiveTo determine an optimal population red blood cell (RBC) folate concentration for the prevention of neural tube birth defects.DesignBayesian model.SettingData from two population based studies in China.Participants247,831 participants in a prospective community intervention project in China (1993-95) to prevent neural tube defects with 400 μg/day folic acid supplementation and 1194 participants in a population based randomized trial (2003-05) to evaluate the effect of folic acid supplementation on blood folate concentration among Chinese women of reproductive age.InterventionFolic acid supplementation (400 μg/day).Main outcome measuresEstimated RBC folate concentration at time of neural tube closure (day 28 of gestation) and risk of neural tube defects.ResultsRisk of neural tube defects was high at the lowest estimated RBC folate concentrations (for example, 25.4 (95% uncertainty interval 20.8 to 31.2) neural tube defects per 10,000 births at 500 nmol/L) and decreased as estimated RBC folate concentration increased. Risk of neural tube defects was substantially attenuated at estimated RBC folate concentrations above about 1000 nmol/L (for example, 6 neural tube defects per 10,000 births at 1180 (1050 to 1340) nmol/L). The modeled dose-response relation was consistent with the existing literature. In addition, neural tube defect risk estimates developed using the proposed model and population level RBC information were consistent with the prevalence of neural tube defects in the US population before and after food fortification with folic acid.ConclusionsA threshold for "optimal" population RBC folate concentration for the prevention of neural tube defects could be defined (for example, approximately 1000 nmol/L). Population based RBC folate concentrations, as a biomarker for risk of neural tube defects, can be used to facilitate evaluation of prevention programs as well as to identify subpopulations at elevated risk for a neural tube defect affected pregnancy due to folate insufficiency.

Dataset Information

Key apoptotic genes APAF1 and CASP9 implicated in recurrent folate-resistant neural tube defects.

Publications

Key apoptotic genes APAF1 and CASP9 implicated in recurrent folate-resistant neural tube defects.

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