International Meeting for Autism Research: Maternally Acting Folate-Related Gene Alleles along with Maternal and Possibly Grandmaternal Folate Status May Contribute to Epigenetic Abnormalities In Autism and Down Syndrome

Maternally Acting Folate-Related Gene Alleles along with Maternal and Possibly Grandmaternal Folate Status May Contribute to Epigenetic Abnormalities In Autism and Down Syndrome

Friday, May 13, 2011: 11:15 AM
Elizabeth Ballroom GH (Manchester Grand Hyatt)
9:45 AM
W. G. Johnson1, S. Buyske2 and E. S. Stenroos3, (1)UMDNJ-RWJMS, Short Hills, NJ, (2)Department of Statistics, Rutgers University, Piscataway, NJ, (3)The Staged Research Building, Room 107, Piscataway, NJ, United States
Background: Maternally acting gene alleles (MAGAs) are known to contribute to autism and other neurodevelopmental disorders directly, and they may contribute indirectly as well through their influence on epigenetic factors. Epigenetic factors are believed to contribute to autism and other neurodevelopmental disorders. MAGAs are a type of maternal effect where maternal alleles contribute to a disorder in the embryo/fetus whether the embryo/fetus inherits the allele or not. From the perspective of the embryo/fetus, MAGAs are an environmental effect. MAGAs may act during pregnancy to contribute to autism, but they may also in principle act before pregnancy.

Objectives: To determine whether MAGAs can act prior to pregnancy, and if so by which mechanisms, to contribute to autism and other neurodevelopmental disabilities in the embryo/fetus.

Methods: We identified reports of maternal genetic effects and excluded those resulting from: maternal environmental effects on the fetus or interacting with fetal genotypes; mitochondrial genes; microchimerism; or known genomic imprinting alone. We included MAGAs affecting phenotype of the embryo/fetus. We determined possible mechanisms of action, considering that genes may have more than one mechanism and considering the possibility of ascertainment bias.

Results: We found 67 reports of MAGAs. Since both autism and Down syndrome (DS) have epigenetic effects that may contribute to the phenotype, we focused on these disorders: 6 reports of MAGAs involved autism and 26 involved DS. Since most non-disjunction in liveborn DS individuals occurs in maternal gametes in the extended first meiotic division (which begins in the mother’s own third month of gestation in utero and ends just before fertilization of the maternal gamete), MAGAs contributing to non-dysjunction in DS must act before pregnancy onset and possibly long before pregnancy onset. 8 MAGAs involved DS, all of them folate-related: MTHFR*C677T, MTHFR*A1298C, MTRR*A66G, RFC1*A80G, TYMS*28bp-repeat-2R, MTHFD1*G1958A, MTR*A2756G, and TC*C776C. 4 MAGAs involved autism, one of them folate-related: RFC1*A60G, GSTP1*313A, HLA*DR4, and C4B*0.

Conclusions: Since folate-related MAGAs were found for both autism and DS, and since folate metabolism contributes through S-adenosylmethionine to biological methylation of DNA as well as that of proteins and lipids, it is possible that alteration of folate metabolism through folate-related MAGAs could contribute to epigenetic abnormalities in both autism and DS and perhaps other neurodevelopmental disorders. Adequate maternal folate status contributes to prevention of chromosome breakage and prevention of DNA hypomethylation. Maternal folate abnormality may contribute to demethylation of heterochromatin and histones and contribute to structural centromeric defects leading to aneuploidy in DS. Maternal folate abnormalities may also contribute to epigenetic abnormalities of imprinted chromosome regions in autism, e.g., maternally derived duplications of the imprinted domains on chromosomes 15q11-13 and 7q leading to parent-of-origin effects.  Effects of folate deficiency in mothers of individuals with autism may be potentiated by the folate-related MAGAs noted earlier to contribute to DS. Evidence suggests that some maternal abnormalities, e.g., the trisomy 21 mosaic carrier state, may originate with the maternal grandmother. Thus, some effects of folate deficiency, potentiated by MAGAs, originate in mothers, and some possibly in maternal grandmothers of individuals with DS and autism.

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