title: Alternative splicing and promoter use in the human GABRA2 gene.
abstract: GABA(A) receptors mediate the majority of the fast synaptic inhibition in the mammalian brain. They are the targets of several important drugs, including benzodiazepines, which are used as anxiolytics, sedatives, anti-convulsants, and in the treatment of alcohol withdrawal symptoms. Non-coding variations in GABRA2, the gene encoding the alpha2 subunit, are associated with the risk for alcoholism, suggesting that regulatory differences are important. GABRA2 mRNAs from whole human brain and from three brain regions were examined for evidence of alternative splicing using reverse transcription-PCR and DNA sequencing. A complex pattern of alternative splicing and alternative promoter use of the human GABRA2 mRNA was demonstrated. There are four major isoforms consisting of combinations of two alternative 5' and 3' exons, as well as minor isoforms lacking exon 4 or exon 8. The alternative 5' exons each lie downstream of a functional promoter sequence, as shown by transient transfection assays. The promoter activities of naturally occurring haplotypes differed, indicating genetic differences in gene expression.
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Room 4063E, Indianapolis, IN 46202-5122, USA.
authors.forename: Huijun
authors.initials: H
authors.lastname: Tian
authors.forename: Hui-Ju
authors.initials: HJ
authors.lastname: Chen
authors.forename: Tiffeny H
authors.initials: TH
authors.lastname: Cross
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Edenberg
mesh_terms: D000437:Alcoholism / Q000235:genetics / Q000378:metabolism; D017398:Alternative Splicing / Q000235:genetics*; D001483:Base Sequence; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D001923:Brain Chemistry / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D005809:Genes, Regulator / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008969:Molecular Sequence Data; D009433:Neural Inhibition / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics*; D013569:Synapses / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: C484841:GABRA2 protein, human; D020033:Protein Isoforms; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid