Article

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

Medical Microbiology and Immunology, Rowe Program in Human Genetics, School of Medicine, University of California, Davis, CA 95616, USA.
Human Molecular Genetics (impact factor: 7.64). 04/2007; 16(6):691-703. DOI:10.1093/hmg/ddm014 pp.691-703
Source: PubMed

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.

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Keywords

21 control brain samples
 
bisulfite sequencing
 
Chromatin immunoprecipitation
 
coding single nucleotide polymorphisms
 
GABRB3 protein expression
 
homologous 15q11-13 pairing
 
imprinted genes
 
maternal 15q11-13 deletions
 
MeCP2 acts
 
MeCP2 binds
 
methylated CpG sites
 
mouse brain
 
normal human cortex
 
optimal expression
 
paternal expression bias
 
Quantitative real-time RT-PCR analysis
 
RTT brain samples
 
SH-SY5Y neuroblastoma cells
 
skewed allelic expression
 
three GABR genes