Human gamma-aminobutyric acid B receptor gene: Complementary DNA cloning, expression chromosomal location, and genomic organization

Background: The 6p21.3 region of human chromosome 6 is a genetic locus for schizophrenia, juvenile myoclonic epilepsy, and dyslexia. Methods: Due to our interest in these disorders we performed complementary DNA (cDNA) hybridization selection on genomic DNA clones spanning this region to identify potential positional-candidate genes. Results: We identified a full- length cDNA with an open reading frame of 2883 bp corresponding to a predicted protein of 961 amino acids that shares greater than 95% homology with the rat gamma-aminobutyric acid B (GABA(B)) receptor. Northern blot hybridization identified a 4.4-kb transcript in human brain. The human gene mapped to two sites on 6p21.3 separated by 2 Mb. Sequence analysis of both sites showed that the centromeric gene is transcribed, whereas the telomeric site is likely a pseudogene. The transcribed gene is distributed over 22 exons spanning 18 kb of genomic DNA. Conclusions: The genomic location, tissue expression, and function of the human GABA(B) receptor gene suggest that it is an important positional-candidate for the neurobehavioral disorders with a genetic locus on 6p21.3. In addition, delineation of the genomic organization will now permit it to be integrated as part of pharmacogenetic studies in trials of anxiolytic, narcotic, antiepileptic, and fluoxetine therapies.