an Alternative-splicing Hot-spot in gabrb2: Novel Splicing Variants Associated with Major Psychotic Disorders

Abstract

GABRB2, the gene for β₂ subunit of the gamma-aminobutyric acid type A (GABA_A) receptor, is known to display two splicing isoforms in the brain, namely β_2L containing Exon 10 and β_2S devoid of Exon 10. Previously, the expressions of these isoforms were correlated with both schizophrenia and various sequence polymorphisms of the gene. in the present study, a series of deletions made on Intron 9 of a minigene construct affected the expression of Exon 10, and generated additional splicing variations suggesting the existence of additional splicing variants of β₂subunit. A search among brain cDNAs uncovered the two novel short forms: β_2S1which is devoid of Exons 10 and 11 and bears an extended Exon 9, and β_2S2 which is devoid of Exon 10 and bears a shortened Exon 11.Real-time quantitative polymerase chain reaction, performed with a cohort of 31 schizophrenics, 30 bipolar disorder and 31 controls of US population, showed that the level of β_2S2 was significantly decreased in bipolar disorder, and marginally decreased in schizophrenia, while β_2S1 was marginally increased in both of these psychotic disorders. Significant genotypic effects of rs1816071, rs1816072 and rs187269 on β_2S2 level were observed in male schizophrenic and bipolar patients. These findings pointed to the neighborhood of Exon 10 as an alternate-splicing hot-spot, and underlined the relevance of β₂ subunit isoforms to the etiology of psychotic disorders.