GABAA receptor β3 subunit gene-deficient heterozygous mice show parent-of-origin and gender-related differences in β3 subunit levels, EEG, and behavior

Liljelund, Patricia; Handforth, Adrian; Homanics, Gregg E.; Olsen, Richard W.

doi:10.1016/j.devbrainres.2005.03.014

Cited by 46 publications

(37 citation statements)

References 61 publications

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“…The hypomethylation of both AS and PWS samples suggests that trans effects between parental alleles serve to regulate proper methylation levels in this locus in cortex. The gender difference in PWS samples for GABRB3 was unexpected, however, Liljelund et al (41), also found gender and parent-of-origin effects on Gabrb3 protein expression in mice heterozygous for a small Gabrb3 deletion that includes a syntenic region for the intron 3 methylation sites. Control and autism brain samples did not exhibit gender effects on methylation and autism samples with loss of biallelic expression did not have methylation defects within the assayed regions of GABRB3 or GABRG3 ( Figure 5).…”

Section: Discussionmentioning

confidence: 99%

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

Hogart

Nagarajan

Patzel

et al. 2007

Human Molecular Genetics

218

173

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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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Section: Discussionmentioning

confidence: 99%

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

Hogart

Nagarajan

Patzel

et al. 2007

Human Molecular Genetics

218

173

View full text Add to dashboard Cite

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“…Mutation of the b3 subunit, GABRB3 (Liljelund et al, 2005), not only produces a mixed seizure pattern with convulsive episodes but also features brief theta frequency discharges eliminated by ethosuximide. In the thalamic nuclei, the b3 subunit is specifically expressed in the RTN (Pirker et al, 2000).…”

Section: Gaba a Receptor Mutations: Fast Synaptic Disinhibitionmentioning

confidence: 99%

Monogenic models of absence epilepsy

Maheshwari

Noebels

2014

Progress in Brain Research

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“…Surviving mice have a reduced lifespan and display hyperactivity, neurological impairment, movement disorder as well as frequent myoclonus and occasional epileptic seizures [124]. The status of Gabrb3 imprinting has been examined in heterozygous Gabrb3-mutant mice [125]. The parentof-origin and gender-related differences in Gabrb3 expression observed in this study [125] were determined by analyzing GABRB3 protein and need to be confirmed by quantitative mRNA analysis in additional animals.…”

mentioning

confidence: 96%

“…The status of Gabrb3 imprinting has been examined in heterozygous Gabrb3-mutant mice [125]. The parentof-origin and gender-related differences in Gabrb3 expression observed in this study [125] were determined by analyzing GABRB3 protein and need to be confirmed by quantitative mRNA analysis in additional animals. There are also reports of a few AS cases that display mutations of the gene encoding methyl CpG binding protein 2 (MeCP2) [126,127].…”

mentioning

confidence: 99%

Molecular epigenetics of Angelman syndrome

Lalande

Calciano

2007

Cell. Mol. Life Sci.

127

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Angelman syndrome (AS) is a neurogenetic disorder characterized by severe mental retardation, ataxia, seizures, EEG abnormalities and bouts of inappropriate laughter. AS individuals fail to inherit a normal active maternal copy of ubiquitin protein ligase E3A (UBE3A). UBE3A is subject to genomic imprinting, with predominant transcription of the maternal allele in brain. The known genetic causes of AS are maternal deletion of chromosome 15q11-q13, paternal chromosome 15 uniparental disomy, UBE3A mutation and an abnormality of the imprinting process, termed imprinting defect. There remain major questions concerning the molecular pathogenesis of AS, including: 1) the mechanisms underlying the imprinting defect class of AS, 2) the identity of proteins targeted by UBE3A, 3) the role of a noncoding antisense transcript in regulating UBE3A imprinting and 4) the contribution of other genes such as methyl-binding CpG-binding protein 2 and gamma-aminobutyric acid A receptor, subunit beta3 to the AS phenotype.

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GABAA receptor β3 subunit gene-deficient heterozygous mice show parent-of-origin and gender-related differences in β3 subunit levels, EEG, and behavior

Cited by 46 publications

References 61 publications

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

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

Monogenic models of absence epilepsy

Molecular epigenetics of Angelman syndrome

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