GABA is the major inhibitory neurotransmitter in the mammalian brain and defects in inhibition have been implicated in autism spectrum disorders. GABA inhibition is mediated through a variety of receptor subunit genes. Three GABAA receptor subunit genes, GABRB3, GABRA5, and GABRG3 are located on chromosome 15q11-13. In addition to GABAA receptor subunit genes, chromosome 15q11-13 contains genes that are expressed based on the parental origin of the chromosome, a process termed genomic imprinting. Due to imprinting, deletions of chromosome 15q11-13 result in two different disorders, Prader-Willi syndrome and Angleman syndrome, depending on the parental origin of the deletion. Additionally maternal duplications of this genomic region are observed in 1-3% of autism cases. Although each of these disorders is clinically distinct, there are similarities in phenotypes, such as seizures, that may be due to improper levels of GABAA receptor genes. Genetic studies of families with autism without a known genetic cause have found evidence that genetic markers in GABRB3 are significantly associated with autism. Although genetic mutations have not been found in GABRB3, significantly reduced levels of GABRB3 protein were found in a majority of autism brain samples. Further studies have shown an abnormal expression pattern of only one parental copy of 15q11-13 GABAA receptor genes in a subset of autism samples. Since no evidence was found for a direct genetic explanation for this abnormal gene expression, we hypothesize that epigenetic changes, heritable modifications to DNA and the proteins that are involved in DNA packaging, may explain the expression abnormalities in autistic brain samples.
ASJC Scopus subject areas