Epigenetics of Autism

Pervasive developmental disorder

Epigenetics [ep-uh-juh-net-iks] refers to non-genetic, heritable characteristics: information other than that found in DNA that can be transmitted from parent to offspring, such as in the form of methylation of DNA (molecular markers attached at several points on a strand of DNA) or histone modification (histones are protein structures that tightly pack and unpack DNA, exposing and ‘expressing’ desired genes).

Autism spectrum disorder (ASD) includes autism, Asperger disorder (high-functioning autism), childhood disintegrative disorder, and pervasive developmental disorder-not otherwise specified.

While the exact cause of ASD has remained somewhat of a mystery, it appears to be genetic in origin. Most data supports a polygenic (several genes working together to influence a phenotypic trait), epistatic (genes at different loci interacting) model, meaning that the disorder is caused by two or more genes and that those genes are interacting in a complex manner. Several genes, between two to fifteen in number, have been identified and could potentially contribute to disease susceptibility.

However, an exact determination of the cause of ASD has yet to be discovered and there probably is not one single genetic cause of any particular set of disorders, leading many researchers to believe that epigenetic mechanisms, such as genomic imprinting or epimutations, may play a major role. Epigenetic mechanisms can contribute to disease phenotypes. Epigenetic modifications like DNA methylation and modifications to histones contribute to regulating gene expression without changing the sequence of the DNA and may be influenced by exposure to environmental factors and may be heritable from parents. Rett syndrome and Fragile X syndrome (FXS) are single gene disorders related to ASD with overlapping symptoms that include deficient neurological development, impaired language and communication, difficulties in social interactions, and stereotyped hand gestures. It is not uncommon for a patient to be diagnosed with both ASD and Rett syndrome and/or FXS. Epigenetic regulatory mechanisms play the central role in pathogenesis of these two diseases.

Genomic imprinting may also contribute to ASD as another example of epigenetic regulation of gene expression (activation or deactivation). In this instance, the epigenetic modification(s) causes the offspring to express the maternal copy of a gene or the paternal copy of a gene, but not both. The imprinted gene is silenced through epigenetic mechanisms. Candidate genes and susceptibility alleles for autism are identified using a combination of techniques, including genome-wide and targeted analyses of allele sharing in sibling pairs. Results from numerous studies have identified several genomic regions known to be subject to imprinting, candidate genes, and gene-environment interactions. Members of the GABA receptor family, especially GABRB3, are attractive candidate genes for Autism because of their function in the nervous system. Gabrb3 null mice exhibit behaviors consistent with autism and multiple genetic studies have found significant evidence for association.

There is a definite gender bias in the distribution of ASD. There are about four times as many affected males across the ASD population. Even when patients with mutations in X-linked genes are excluded, the gender bias remains. However, when only looking at patients with the most severe cognitive impairment, the gender bias is not as extreme. While the most obvious conclusion is that an X-linked gene of major effect is involved in contributing to ASD, the mechanism appears to be much more complex and perhaps epigenetic in origin. Based on the results of a study on females with Turner syndrome (a genetic condition in which a female does not have the usual pair of two X chromosomes), a hypothesis involving epigenetic mechanisms was proposed to help describe the gender bias of ASD.

Turner syndrome patients have only one X chromosome which can be either maternal or paternal in origin. When 80 females with monosomy X were tested for measures of social cognition, the patients with a paternally derived X chromosome performed better than those with a maternally derived X chromosome. Males have only one X chromosome, derived from their mother. If a gene on the paternal X chromosome confers improved social skills, males are deficient in the gene. This could explain why males are more likely to be diagnosed with ASD. In the proposed model, the candidate gene is silenced on the maternal copy of the X chromosome. Thus, males do not express this gene and are more susceptible to subsequent impairments in social and communication skills. Females, on the other hand, are more resistant to ASD.

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