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Abstract
BackgroundNon-coding single nucleotide polymorphisms (SNPs) in GABRB2, the gene for β2-subunit of gamma-aminobutyric acid type A (GABAA) receptor, have been associated with schizophrenia (SCZ) and quantitatively correlated to mRNA expression and alternative splicing.Methods and FindingsExpression of the Exon 10 region of GABRB2 from minigene constructs revealed this region to be an “alternative splicing hotspot” that readily gave rise to differently spliced isoforms depending on intron sequences. This led to a search in human brain cDNA libraries, and the discovery of two novel isoforms, β2S1 and β2S2, bearing variations in the neighborhood of Exon-10. Quantitative real-time PCR analysis of postmortem brain samples showed increased β2S1 expression and decreased β2S2 expression in both SCZ and bipolar disorder (BPD) compared to controls. Disease-control differences were significantly correlated with SNP rs187269 in BPD males for both β2S1 and β2S2 expressions, and significantly correlated with SNPs rs2546620 and rs187269 in SCZ males for β2S2 expression. Moreover, site-directed mutagenesis indicated that Thr365, a potential phosphorylation site in Exon-10, played a key role in determining the time profile of the ATP-dependent electrophysiological current run-down.ConclusionThis study therefore provided experimental evidence for the importance of non-coding sequences in the Exon-10 region in GABRB2 with respect to β2-subunit splicing diversity and the etiologies of SCZ and BPD.
Highlights
Introduction cAminobutyric acid (GABA) is the major inhibitory amino acid neurotransmitter in the vertebrate nervous system
The molecular heterogeneity of gammaaminobutyric acid type A (GABAA) receptor subunits is further increased by the alternative splicing of some subunit mRNAs, producing at least two isoforms of each of the a6, b2, b3 and c2 subunits [3]
Most GABAA receptors are composed of two a subunits, two b2 subunits and one c subunit [4]
Summary
Introduction cAminobutyric acid (GABA) is the major inhibitory amino acid neurotransmitter in the vertebrate nervous system. Subtypes of GABAA receptors are assembled from pentameric combinations of a1-a6, b1-b3, c1-c3, r1-r3, e, d and p subunits [1,2]. The molecular heterogeneity of GABAA receptor subunits is further increased by the alternative splicing of some subunit mRNAs, producing at least two isoforms of each of the a6, b2, b3 and c2 subunits [3]. The b2 subunit gene products of human GABRB2 expressed from cDNA library are found in two alternatively spliced isoforms, the short form b2S and the long form b2L. Non-coding single nucleotide polymorphisms (SNPs) in GABRB2, the gene for b2-subunit of gammaaminobutyric acid type A (GABAA) receptor, have been associated with schizophrenia (SCZ) and quantitatively correlated to mRNA expression and alternative splicing
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