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

Article (PDF Available)inAmerican Journal of Medical Genetics Part B Neuropsychiatric Genetics 153B(6):1209-20 · September 2010with47 Reads
DOI: 10.1002/ajmg.b.31094 · Source: PubMed
  • 43.18 · University of Arkansas for Medical Sciences
  • 37.29 · University of Arkansas for Medical Sciences
  • 25.23 · University of Arkansas for Medical Sciences
  • 42.89 · University of Arkansas for Medical Sciences
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.


    • "Folic acid is the inactive, oxidized form of folate compounds that is important for many physiological systems of the body. Folate is the major one-carbon donor for de novo nucleotide synthesis for DNA replication and also for remethylation of homocysteine to methionine for essential methylation reactions [29]. The folate cycle interacts with the methionine cycle as well as the tetrahydrobiopterin construction and salvage pathways. "
    [Show abstract] [Hide abstract] ABSTRACT: Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with complex genetic etiology. Recent studies have indicated that children with ASD may have altered folate or methionine metabolism, suggesting that the folate-methionine cycle may play a key role in the etiology of ASD. SLC19A1, also referred to as reduced folate carrier 1 (RFC1), is a member of the solute carrier group of transporters and is one of the key enzymes in the folate metabolism pathway. Findings from multiple genomic screens suggest the presence of an autism susceptibility locus on chromosome 21q22.3, which includes SLC19A1. Therefore, we performed a case-control study in a Japanese population. In this study, DNA samples obtained from 147 ASD patients at the Kanazawa University Hospital in Japan and 150 unrelated healthy Japanese volunteers were examined by the sequence-specific primer-polymerase chain reaction method pooled with fluorescence correlation spectroscopy. p < 0.05 was considered to represent a statistically significant outcome. Of 13 single nucleotide polymorphisms (SNPs) examined, a significant p-value was obtained for AA genotype of one SNP (rs1023159, OR = 0.39, 95% CI = 0.16-0.91, p = 0.0394; Fisher's exact test). Despite some conflicting results, our findings supported a role for the polymorphism rs1023159 of the SLC19A1 gene, alone or in combination, as a risk factor for ASD. However, the findings were not consistent after multiple testing corrections. In conclusion, although our results supported a role of the SLC19A1 gene in the etiology of ASD, it was not a significant risk factor for the ASD samples analyzed in this study.
    Full-text · Article · May 2016
    • "According to the Institute of Medicine (US) of the National Academy of Sciences [1998] and published research [Bailey and Gregory, 1999] , the dietary reference intake for adults in general is 400 μg Pte- Glu per day, for pregnant women 600 μg per day and for breastfeeding women 500 μg per day. Given the fortification of grain-based foods, the oral supplementation, and the recognized diversity of human metabolic genotypes and phenotypes [James et al., 2006[James et al., , 2010 , overconsumption of PteGlu is a serious issue [reviewed by Crider et al., 2011; Choi et al., 2014] . It is conceivable that the prophylactic overconsumption of PteGlu to prevent neural tube defects may be related to adverse interferences with single-carbon metabolism. "
    [Show abstract] [Hide abstract] ABSTRACT: The vitamin folic acid (FA) is essential for DNA synthesis, repair and methylation, and for methionine synthesis. Although it is necessary for neural development, recent studies suggest a possible link between excess maternal supplemental FA intake and adverse interferences with single-carbon metabolism and neural development. Insufficient FA early in brain development can lead to failure of the neural tube closure, but the consequences of too much intake have not been fully investigated. Plasma FA concentrations can increase greatly with dietary supplementation. To model the development of neural connectivity, we cultured dorsal root ganglia (DRGs) taken from 8-day-old chick embryos in a range of pteroylmonoglutamate (PteGlu, synthetic supplemental FA) concentrations. DRGs were cultured for 36 h, fixed and immunostained to reveal the locations of neural networks with synaptic vesicles. We found a concentration-dependent relationship with significant reduction in neurite length in PteGlu concentrations from 0.25 to 20 μM. The average total of stained synaptic areas surrounding each cultured DRG was significantly reduced as well. To further characterize the effects, we carried out time-lapse imaging of growth cones at terminals of extending neurites. We found that PteGlu reduced the area-changing activity of the growth cone, hindering its exploratory capabilities, along with a tendency to inhibit overall advancement, thus altering the ability to extend and form synapses. Our results show that PteGlu at 250 nM and higher reduces neurite extension and synapse formation in a dose-dependent manner during neurogenesis, and that its effect is mediated through inhibition of growth cone motility.
    Full-text · Article · May 2016
    • "Analysis of 5-methylcytosine (5-mC) and 5-hydroxy- methylcytosine (5-hmC) levels RNaseA (Sigma-Aldrich, St. Louis, MO) 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). The detailed methodology can be found in the Supplementary Material. "
    [Show abstract] [Hide abstract] ABSTRACT: Evidence continues to grow on potential environmental health hazards associated with engineered nanomaterials (ENMs). While the geno- and cytotoxic effects of ENMs have been investigated, their potential to target the epigenome remains largely unknown. The aim of this study is two-fold: 1) determining whether or not industry relevant ENMs can affect the epigenome in vivo and 2) validating a recently developed in vitro epigenetic screening platform for inhaled ENMs. Laser printer-emitted engineered nanoparticles (PEPs) released from nano-enabled toners during consumer use and copper oxide (CuO) were chosen since these particles induced significant epigenetic changes in a recent in vitro companion study. In this study, the epigenetic alterations in lung tissue, alveolar macrophages and peripheral blood from intratracheally instilled mice were evaluated. The methylation of global DNA and transposable elements (TEs), the expression of the DNA methylation machinery and TEs, in addition to general toxicological effects in the lung were assessed. CuO exhibited higher cell-damaging potential to the lung, while PEPs showed a greater ability to target the epigenome. Alterations in the methylation status of global DNA and TEs, and expression of TEs and DNA machinery in mouse lung were observed after exposure to CuO and PEPs. Additionally, epigenetic changes were detected in the peripheral blood after PEPs exposure. Altogether, CuO and PEPs can induce epigenetic alterations in a mouse experimental model, which in turn confirms that the recently developed in vitro epigenetic platform using macrophage and epithelial cell lines can be successfully utilized in the epigenetic screening of ENMs.
    Full-text · Article · Nov 2015
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