In addition, two mutations in the s

In addition, two mutations in the signal peptide of the b3-v2 subunit, P11S and S15F, caused reductions in GABAA receptor current density when expressed as a1b3-v2(P11S)g2S or a1b3-v2(S15F)g2S receptors and compared to wild-type receptors (a1b3-v2g2S). Similarly, cells expressing receptors containing a b3-v2 subunit mutation just beyond the signal peptide in exon 2, a1b3-v2(G32R)g2S, also had smaller GABA-evoked current density than did cells expressing wild-type receptors. This is important because as a ligand-gated, chloride-selective ion channel, the function of the GABAA receptor is to provide the majority of synaptic inhibition in the central nervous system. GABAR expression and kinetic properties are determined by the subunit combination present in the receptor.Although there are numerous genes that encode for subunits and subunit subtypes of the GABAA receptor (a1-6,b1-3, g1-3, d, 3, q, and p), the majority of the GABAA receptors in the central nervous system are composed of two a,two b, and a single g or d subunit.42,43 To date, several mutations have been identified in the a1, g2, and d subunits of the GABAA receptor associated with familial epilepsy syndromes. Although these families were classified under the generalized epilepsy with febrile seizures plus (GEFSþ) (febrile and afebrile seizures) spectrum of epilepsy or juvenile myoclonic epilepsy, all had childhood absence seizures as a phenotype. These observations strongly suggest that GABAR might be the crucial pathogenic molecule for childhood absence epilepsy.44 The majority of these published GABAR mutations also cause altered subunit trafficking and, subsequently, expression of the mutated subunit,and others alter the function of the ion channel.