Analysis of the Set of GABAA Receptor Genes in the Human Genome

The genes of the ionotropic gamma-aminobutyric acid receptor (GABR) subunits have shown an unusual chromosomal clustering, but only now can this be fully specified by analyses of the human genome. We have characterized the genes encoding the 18 known human GABR subunits, plus one now located here, for their precise locations, sizes, and exon/intron structures. Clusters of 17 of the 19, distributed between five chromosomes, are specified in detail, and their possible significance is considered. By applying search algorithms designed to recognize sequences of all known GABR-type subunits in species from man down to nematodes, we found no new GABR subunit is detectable in the human genome. However, the sequence of the human orthologue of the rat GABR rho3 receptor subunit was uncovered by these algorithms, and its gene could be analyzed. Consistent with those search results, orthologues of the beta4 and gamma4 subunits from the chicken, not cloned from mammals, were not detectable in the human genome by specific searches for them. The relationships are consistent with the mammalian subunit being derived from the beta line and epsilon from the gamma line, with mammalian loss of beta4 and gamma4. In their structures the human GABR genes show a basic pattern of nine coding exons, with six different genomic mechanisms for the alternative splicing found in various subunits. Additional noncoding exons occur for certain subunits, which can be regulatory. A dicysteine loop and its exon show remarkable constancy between all GABR subunits and species, of deduced functional significance.