First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma 2-subunit gene

Major advances in the identification of genes implicated in idiopathic epil epsy have been made. Generalized epilepsy with febrile seizures plus (GEFS), benign familiar neonatal convulsions and nocturnal frontal lobe epilepsy , three autosomal dominant idiopathic epilepsies, result from mutations aff ecting voltage-gated sodium and potassium channels, and nicotinic acetylcho line receptors, respectively(1-6), Disruption of GABAergic neurotransmissio n mediated by gamma -aminobutyric acid (GABA) has been implicated in epilep sy for many decades(7). We now report a K289M mutation in the GABA(A) recep tor gamma2-subunit gene (GABRG2) that segregates in a family with a phenoty pe closely related to GEFS+ (ref. 8), an autosomal dominant disorder associ ating febrile seizures and generalized epilepsy previously linked to mutati ons in sodium channel genes(1,2). The K289M mutation affects a highly conse rved residue located in the extracellular loop between transmembrane segmen ts M2 and M3. Analysis of the mutated and wild-type alleles in Xenopus laev is oocytes confirmed the predicted effect of the mutation, a decrease in th e amplitude of GABA-activated currents. We thus provide the first genetic e vidence that a GABA(A) receptor is directly involved in human idiopathic ep ilepsy.