GABRB3

Official Full Name

gamma-aminobutyric acid type A receptor subunit beta3

Organism

Homo sapiens

GeneID

2562

Background

This gene encodes a member of the ligand-gated ionic channel family. The encoded protein is one the subunits of a multi-subunit chloride channel that serves as the receptor for gamma-aminobutyric acid, a major inhibitory neurotransmitter of the mammalian nervous system. This gene is located on the long arm of chromosome 15 in a cluster with two other genes encoding related subunits of the family. This gene may be associated with the pathogenesis of several disorders including Angelman syndrome, Prader-Willi syndrome, nonsyndromic orofacial clefts, epilepsy and autism. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2013]

Synonyms

ECA5; DEE43; EIEE43;

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Detailed Information

Gamma-aminobutyric acid type A (GABAA) receptors are ligand-gated chloride channels which act as the primary mediators of fast inhibitory synaptic transmission in the central nervous system. Up to now, several genetic epilepsy syndromes have been associated with variants in GABAA receptor subunit genes including GABRA1, GABRB3, GABRD, and GABRG2. GABRB3, located on chromosome 15q11.2-q12, encodes the β3-subunit of the GABAA receptor. Reduced GABRB3 expression has been postulated in the abnormal sensory processing, pathogenesis of absence seizures, and other neurodevelopmental disorder phenotypes such as Angelman syndrome, intellectual disability and autism spectrum disorders. Moreover, single nucleotide polymorphisms and missense mutations in GABRB3 have been implicated in childhood absence epilepsy.

Epigenetic modulation of GABRB3

Two NRSF binding motifs are found in GABRB3, one about 400 bp upstream from exon 1A, and the other within intron 3, both locations corresponding to predicted RE1 sites. NRSF, also known as repressor element 1 (RE1)-silencing transcription factor (REST), is an essential epigenetic modulator for neuronal differentiation, plasticity and homeostasis. Deregulation of REST and ncRNAs are implicated in cancer and neurodevelopmental diseases, including epilepsy.

The expression of GABRB3 that has two RE1/NRSE sites is regulated by REST. Furthermore, Hogart et al. found a MeCP2 binding site in intron 3 of GABRB3 close to the RE1. MeCP2, a methylated DNA binding protein, is an epigenetic regulator that is required for development and maintenance of neurons. They also find that GABRB3 expression is biallelic but paternally biased in human prefrontal cortex (Brodmann field 9) through MeCP2 activation of GABRB3 expression. That is to say, REST, which connects with various co-factors including MeCP2, could modulate GABRB3 expression in tissue-specific development, age-dependent, not only in stem cells, but also in mature neurons through environmental stimulation that could occur throughout the lifespan.

GABRB3 and neurodevelopmental disorders

Various animal studies, clinical reports, genetic association and basic molecular studies have provided evidence that GABRB3 is involved in developmental neurological disorders. Three missense mutations (G32A, P11S and S15F) found in an alternative signal peptide and the N-terminus of GABRB3, segregated with remitting childhood absence epilepsy (rCAE) within four families. Two multiplex and multigeneration families containing eight affected members and one proband of a singleton have mutations in an alternative signal peptide. These studies showed that the functional abnormality resulting from missense mutations, as well as certain combinations of SNPs in multiple regulatory elements in the 5’region of GABRB3, causes reduced expression of GABRB3, and a concurrent reduction in inhibition, leading to an increase in susceptibility to absence seizures. The CAE disease phenotype exhibits paternal transmission of the rare GABRB3 signal peptide variant (rs 25409: P11S), whereas maternal transmission of the same variant appears to be associated with autism.

Disruption of GABRB3 causes ocular hypopigmentation

Reduced ocular pigmentation is common in Prader-Willi syndrome (PWS) and Angelman syndrome (AS) and is long thought to be caused by OCA2 deletion. GABRB3 is located in the 15q11-13 region flanked by UBE3A, GABRA5, GABRG3, and OCA2. A recent study report a very robust phenotype in the mouse in which deletion of Gabrb3 alone through disruption of its promoter and exons 1–3 caused almost complete loss of eye pigmentation. With electronic microscopy, it was demonstrated that melanosomes in the mutants were atrophied, and almost no mature melanosomes were detected in the retinal pigment cells in the homozygous Gabrb3^-/- mouse eyes, while mature melanosomes were reduced in the heterozygous Gabrb3^-/- mouse eyes. Moreover, it was confirmed with exome sequencing and transcriptome analysis RNA sequencing (RNA-seq) that Gabrb3 was the only gene which was disrupted in this model while Oca2 gene structure was intact. Disruption of the Gabrb3 promoter with small interfering RNAs (siRNAs) also downregulated the transcripts of Oca2 in mouse neuronal cultures. Thus, this suggests a mechanism in which deletion of Gabrb3, but not Oca2, also could lead to the failure of melanin transport by downregulating Oca2 transcription, thus resulting in hypopigmentation (Figure 1). This extends the biological role of GABRB3 beyond epilepsy and autism and provides crucial insights into understanding the visual defects in AS and PWS.

Figure 1. Disruption of Gabrb3 alone causes profound loss of retinal pigmentation via downregulation of Oca2 transcription.

References:

Delahanty R J, et al. Beyond Epilepsy and Autism: Disruption of GABRB3 Causes Ocular Hypopigmentation. Cell Reports, 2016, 17(12):3115-3124.
Papandreou A, et al. GABRB3 mutations: a new and emerging cause of early infantile epileptic encephalopathy. Developmental Medicine & Child Neurology, 2016, 58(4):416-420.
Tanaka M, et al. GABRB3, epilepsy, and neurodevelopment. Epilepsia, 2011, 51(s5):77-77.
Chen C H, et al. Genetic analysis of GABRB3 as a candidate gene of autism spectrum disorders. Molecular Autism,5,1(2014-06-25), 2014, 5(1):36.
Huang C C, et al. Genetic analysis of GABRB3 at 15q12 as a candidate gene of schizophrenia. Psychiatr Genet, 2014, 24(4):151-157.
Teresa T, et al. Variation in the autism candidate geneGABRB3modulates tactile sensitivity in typically developing children. Molecular Autism,3,1(2012-07-06), 2012, 3(1):6-6.

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