PHENOTYPIC CONSEQUENCES OF DELETION OF THE GAMMA(3)-SUBUNIT, ALPHA(5)-SUBUNIT, OR BETA(3)-SUBUNIT OF THE TYPE-A GAMMA-AMINOBUTYRIC-ACID RECEPTOR IN MICE

Three genes (Gabrg3, Gabra5, and Gabrb3) encoding the gamma3, alpha5, and beta3 subunits of the type A gamma-aminobutyric acid receptor, respectively, are known to map near the pink-eyed dilution (p) locus in mouse chromosome 7. This region shares homology with a segment of human chromosome 15 that is implicated in Angelman syndrome, an inherited neurobehavioral disorder. By mapping Gabrg3 on a panel of p-locus deletions, we have determined that the order of genes within this cluster is centromere-p(D15S12h)-Gabrg3-Gabra5-Gabrb-3-telomere. Like Gabrb3, neither the Gabra5 nor Gabrg3 gene is functionally imprinted in adult mouse brain. Mice deleted for all three subunits die at birth with a cleft palate, although there are rare survivors (almost-equal-to 5%) that do not have a cleft palate but do exhibit a neurological abnormality characterized by tremor, jerky gait, and runtiness. We have previously suggested that deficiency of the beta3 subunit may be responsible for the clefting defect. Most notably, however, in this report we describe mice carrying two overlapping, complementing p deletions that fail to express the gamma3 transcript, as well as mice from another line that express neither the gamma3 nor alpha5 transcripts. Surprisingly, mice from both of these lines are phenotypically normal and do not exhibit any of the neurological symptoms characteristic of the rare survivors that are deleted for all three (gamma3, alpha5, and beta3) subunits. These mice therefore provide a whole-organism type A gamma-aminobutyric-acid receptor background that is devoid of any receptor subtypes that normally contain the gamma3 and/or alpha5 subunits. The absence of an overt neurological phenotype in mice lacking the gamma3 and/or alpha5 subunits also suggests that mutations in these genes are unlikely to provide useful animal models for Angelman syndrome in humans.