Alternative-splicing in the exon-10 region of GABA(A) receptor beta(2) subunit gene: relationships between novel isoforms and psychotic disorders.
BACKGROUND
Non-coding single nucleotide polymorphisms (SNPs) in GABRB2, the gene for beta(2)-subunit of gamma-aminobutyric acid type A (GABA(A)) receptor, have been associated with schizophrenia (SCZ) and quantitatively correlated to mRNA expression and alternative splicing.


RESULTS
Expression 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, beta(2S1) and beta(2S2), bearing variations in the neighborhood of Exon-10. Quantitative real-time PCR analysis of postmortem brain samples showed increased beta(2S1) expression and decreased beta(2S2) 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 beta(2S1) and beta(2S2) expressions, and significantly correlated with SNPs rs2546620 and rs187269 in SCZ males for beta(2S2) expression. Moreover, site-directed mutagenesis indicated that Thr(365), a potential phosphorylation site in Exon-10, played a key role in determining the time profile of the ATP-dependent electrophysiological current run-down.


CONCLUSIONS
This study therefore provided experimental evidence for the importance of non-coding sequences in the Exon-10 region in GABRB2 with respect to beta(2)-subunit splicing diversity and the etiologies of SCZ and BPD.
Zhao
Cunyou
C
Department of Biochemistry and Applied Genomics Center, Fok Ying Tung Graduate School, The Hong Kong University of Science & Technology, Clear Water Bay, Hong Kong, China.
Xu
Zhiwen
Z
Wang
Feng
F
Chen
Jianhuan
J
Ng
Siu-Kin
SK
Wong
Pak-Wing
PW
Yu
Zhiliang
Z
Pun
Frank W
FW
Ren
Lihuan
L
Lo
Wing-Sze
WS
Tsang
Shui-Ying
SY
Xue
Hong
H
D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D001714:Bipolar Disorder / Q000235:genetics; D001921:Brain / Q000378:metabolism / Q000473:pathology; D005091:Exons; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms; D011618:Psychotic Disorders / Q000235:genetics*; D011963:Receptors, GABA-A / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics; D012689:Sequence Homology, Nucleic Acid
D020033:Protein Isoforms; D011963:Receptors, GABA-A