A Functional Polymorphism in the Reduced Folate Carrier Gene and DNA Hypomethylation in Mothers of Children With Autism

Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics (Impact Factor: 3.42). 09/2010; 153B(6):1209-20. DOI: 10.1002/ajmg.b.31094
Source: PubMed


The biologic basis of autism is complex and is thought to involve multiple and variable gene-environment interactions. While the logical focus has been on the affected child, the impact of maternal genetics on intrauterine microenvironment during pivotal developmental windows could be substantial. Folate-dependent one carbon metabolism is a highly polymorphic pathway that regulates the distribution of one-carbon derivatives between DNA synthesis (proliferation) and DNA methylation (cell-specific gene expression and differentiation). These pathways are essential to support the programmed shifts between proliferation and differentiation during embryogenesis and organogenesis. Maternal genetic variants that compromise intrauterine availability of folate derivatives could alter fetal cell trajectories and disrupt normal neurodevelopment. In this investigation, the frequency of common functional polymorphisms in the folate pathway was investigated in a large population-based sample of autism case-parent triads. In case-control analysis, a significant increase in the reduced folate carrier (RFC1) G allele frequency was found among case mothers, but not among fathers or affected children. Subsequent log linear analysis of the RFC1 A80G genotype within family trios revealed that the maternal G allele was associated with a significant increase in risk of autism whereas the inherited genotype of the child was not. Further, maternal DNA from the autism mothers was found to be significantly hypomethylated relative to reference control DNA. Metabolic profiling indicated that plasma homocysteine, adenosine, and S-adenosylhomocyteine were significantly elevated among autism mothers consistent with reduced methylation capacity and DNA hypomethylation. Together, these results suggest that the maternal genetics/epigenetics may influence fetal predisposition to autism.

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    • "RNaseA (Sigma) was added to 1 mg of genomic DNA to a final concentration of 0.02 mg/mL and incubated at 37 C for 15 min. Purified DNA was digested into component nucleotides using Nuclease P1, snake venom phosphodiesterase and alkaline phosphatase as previously described (James et al., 2010). Methodology has been described in the Supplementary materials. "
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    • "Apart from a polymorphism in the reduced folate carrier (RFC1) gene (James et al. 2010), studies of human genetic variation relevant to the methyl donor cycle has largely focused on the methylenetetrahydrofolate reductase (MTHFR) locus. Low blood FA concentrations are associated with a low intake of FA and in persons homozygous for the C667T variant of MTHFR (Anderson et al., 2013). "
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