Human chromosomal localization of genes encoding the gamma 1 and gamma 2 subunits of the gamma-aminobutyric acid receptor indicates that members of this gene family are often clustered in the genome.

The gamma-aminobutyric acid (GABA) receptors are the major inhibitory neurotransmitter receptors in the brain and the site of action of a number of important pharmacological agents including barbiturates, benzodiazepines, and ethanol. The gamma 1 and gamma 2 subunits have been shown to be important in mediating responses to benzodiazepines, and a splicing variant of the gamma 2 subunit, gamma 2L, has been shown to be necessary for ethanol actions on the receptor, raising the possibility that the gamma 2 gene may be involved in human genetic predisposition to the development of alcoholism. We have assigned the human genes encoding the gamma 1 and gamma 2 subunits of the GABAA receptor to chromosomes 4 and 5, respectively, by PCR amplification of human-specific products from human-hamster somatic cell hybrid DNAs. Using panels of chromosome-specific natural deletion hybrids, we have further localized the gamma 1 gene (GABRG1) to 4p14-q21.1 and the gamma 2 gene (GABRG2) to 5q31.1-q33.2. These data indicate that the gamma 1 gene may be clustered together with the previously mapped alpha 2 and beta 1 genes on chromosome 4 and that the gamma 2 gene may be close to the previously localized alpha 1 gene on chromosome 5. To further examine the latter possibility the alpha 1 gene was mapped using the chromosome 5 deletion hybrids and shown to be within the same region as the gamma 2 gene, 5q31.1-q33.2. A PCR-based screening strategy was used to isolate a 450-kilobase human genomic yeast artificial chromosome clone containing both the alpha 1 and gamma 2 genes. Pulsed-field gel restriction mapping of the yeast artificial chromosome indicates that the two genes are within 200 kilobases of each other. The data presented here provide further evidence for the nonrandom organization of the human genome by demonstrating that members of the GABAA receptor gene family often occur in small gene clusters widely distributed in the genome. IMAGES:

γ-氨基丁酸（gamma-aminobutyric acid, GABA）受体是大脑中主要的抑制性神经递质受体，同时也是多种重要药理学制剂的作用靶点，涵盖巴比妥类、苯二氮䓬类物质及乙醇。已有研究证实，γ1和γ2亚基在介导苯二氮䓬类药物的应答反应中发挥关键作用；而γ2亚基的剪接变体γ2L被证明是乙醇作用于该受体的必要条件，这提示γ2基因可能参与人类酗酒的遗传易感性。我们通过对人-仓鼠体细胞杂交DNA中的人源特异性片段进行聚合酶链式反应（PCR）扩增，将编码γ-氨基丁酸A型（GABAA）受体γ1和γ2亚基的人类基因分别定位于4号和5号染色体。利用染色体特异性自然缺失杂交细胞系组，我们进一步将γ1基因（GABRG1）定位至4p14-q21.1区域，将γ2基因（GABRG2）定位至5q31.1-q33.2区域。上述结果表明，γ1基因可能与此前已定位的4号染色体上的α2和β1基因成簇分布；而γ2基因则可能与5号染色体上已定位的α1基因相邻。为进一步验证这一推测，我们利用5号染色体缺失杂交细胞系对α1基因进行了定位，证实其与γ2基因同处于5q31.1-q33.2区域。我们采用基于PCR的筛选策略，分离得到了一个包含α1和γ2基因的450千碱基对人类基因组酵母人工染色体（yeast artificial chromosome, YAC）克隆。对该酵母人工染色体进行的脉冲场凝胶限制性酶切图谱分析显示，这两个基因之间的间距不超过200千碱基对。本文所呈现的数据进一步佐证了人类基因组的非随机组织特性：GABAA受体基因家族的成员通常以广泛分布于基因组各处的小型基因簇形式存在。IMAGES: