THESIS
2008
xvi, 148 leaves : ill. (some col.) ; 30 cm
Abstract
Single nucleotide polymorphisms (SNPs) in type A γ-aminobutyric acid (GABA
A) receptor β
2 subunit gene (GABRB2) were found to be associated with schizophrenia in Chinese, German, Japanese and Portuguese. To explore the potential functional consequences of these DNA sequence polymorphisms, this study examined the expression and electrophysiological properties of alternatively spliced products of GABRB2 along with genotypical disease-association analysis. Real-time quantitative PCR, performed with a US population of 31 schizophrenics, 30 bipolar disorders and 31 controls showed 21.7% reduction in the expression of the long isoform β
2L, and 13.4% in the short isoform β
2S (dominant isoform) in postmortem schizophrenic brain, but not in bipolar disorder’s brain. Furthermore, two novel short i...[
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Single nucleotide polymorphisms (SNPs) in type A γ-aminobutyric acid (GABA
A) receptor β
2 subunit gene (GABRB2) were found to be associated with schizophrenia in Chinese, German, Japanese and Portuguese. To explore the potential functional consequences of these DNA sequence polymorphisms, this study examined the expression and electrophysiological properties of alternatively spliced products of GABRB2 along with genotypical disease-association analysis. Real-time quantitative PCR, performed with a US population of 31 schizophrenics, 30 bipolar disorders and 31 controls showed 21.7% reduction in the expression of the long isoform β
2L, and 13.4% in the short isoform β
2S (dominant isoform) in postmortem schizophrenic brain, but not in bipolar disorder’s brain. Furthermore, two novel short isoforms, β
2S1 and β
2S2, from human brain were observed and characterized. The expression of β
2S2, bearing a frame-shift deletion in the terminal Exon-11, was decreased in schizophrenia (by 17.9%) and bipolar disorders (by 22.5%). The expression of the less abundant β
2S1 was marginally increased in both of these mental disorders (by 43.0% in schizophrenics; by 43.7 % in bipolar disorders). Moreover, the relative expressions of β
2L over β
2S were significantly decreased, suggesting the occurrence of altered splicing, in schizophrenia. In male schizophrenics, the heterozygous genotypes of rs1876071 (T/C) and rs1876072 (A/G) were correlated with reduced expression of β
2L and β
2S, and the heterozygous of rs2546620 (A/G) and homozygous-minor of rs1876071 (C/C) and rs1876072 (G/G) were correlated with reduced expression of β
2S2. In male bipolar disorders, the heterozygous genotypes of rs187269 (T/C) were correlated with reduced expression of β
2S2 as well as the β
2S2/β
2S ratio. Electrophysiologically, the EC
50 for neurotransmitter GABA was significantly reduced with β
2S1, potentially compensating for the GABA deficit observed in schizophrenia. The results thus revealed genotype-dependent expression of the alternatively spliced isoforms of GABA
A receptor β
2 subunit, giving rise to electrophysiological consequences that could play an important role in the pathogenesis mechanism of schizophrenia.
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