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 GABA(A) 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 GABA(A) receptor gene family often occur in small gene clusters widely distributed in the genome.