15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders

Abstract

Human chromosome 15q11-13 is a complex locus containing imprinted genes as well as a cluster of three GABA A receptor subunit (GABR) genes, GABRB3, GABRA5, and GABRG3. Deletion or duplication of 15q11-13 GABR genes occurs in multiple human neurodevelopmental disorders including Prader-Willi syndrome (PWS), Angelman syndrome (AS), and autism. GABRB3 protein expression is also reduced in Rett syndrome (RTT), caused by mutations in MECP2 on Xq28. Although Gabrb3 is biallelically expressed in mouse brain, conflicting data exist regarding the imprinting status of the 15q11-13 GABR genes in humans. Using coding single nucleotide polymorphisms we show that all three GABR genes are biallelically expressed in 21 control brain samples, demonstrating that these genes are not imprinted in normal human cortex. Interestingly, four of eight autism and one of five RTT brain samples showed monoallelic or highly skewed allelic expression of one or more GABR gene, suggesting that epigenetic dysregulation of these genes is common to both disorders. Quantitative real-time RT-PCR analysis of PWS and AS samples with paternal and maternal 15q11-13 deletions revealed a paternal expression bias of GABRB3, while RTT brain samples showed a significant reduction in GABRB3 and UBE3A. Chromatin immunoprecipitation and bisulfite sequencing in SH-SY5Y neuroblastoma cells demonstrated that MeCP2 binds to methylated CpG sites within GABRB3. Our previous studies demonstrated that homologous 15q11-13 pairing in neurons was dependent on MeCP2 and was disrupted in RTT and autism cortex. Combined these results suggest that MeCP2 acts as a chromatin organizer for optimal expression of both alleles of GABRB3 in neurons.

Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders

“…Epigenetic dysregulations affecting the genes encoding GABA A receptors in the brains of individuals with 15q11-q13 copy number abnormalities have been reported previously. 26 The second structural anomaly that was considered as probably causative is a deletion of the 9p24 region. Deletions encompassing this region, which are usually de novo but larger in size (Supplementary Figure S3), are known to cause the 9p deletion syndrome, a disorder characterized by ID, trigonocephaly, facial dysmorphism and sexual reversion in males.…”

Advances in behavioral genetics: mouse models of autism

“…In the case of autism, epigenetic differences may underlie enhanced susceptibility for the disease, through possible mechanisms such as altered MECP2 regulation of GABA A receptor subunit genes through DNA methylation, 309 or aberrant histone acetylation following exposure to a viral agent or neurotoxin, such as valproic acid. 268 Differential epigenetic modifications may explain why individuals with similar, or even identical, genotypes may be discordant for the autism phenotype.…”

Sex Difference in Mecp2 Expression During a Critical Period of Rat Brain Development

“…For example, MeCP2 deficient human and mouse brain exhibit reduced UBE3A and GABRB3 expression; human RTT brain samples also exhibit significantly reduced GABRB3 and UBE3A 2 and some autistic brain samples have abnormalities in GABR gene expression. 31 The phenotypic overlap between these disorders and the apparent control of chromosome 15, UBE3A and GABRB3 implicates MeCP2 as a molecular link between these related pathologies. It also suggests potential parallels with mecp2 sexual dimorphism.…”