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

• Published in: Nature genetics Vol. 28; no. 1; pp. 46 - 48
• Main Authors: Baulac, S, Huberfeld, G, Gourfinkel-An, I, Mitropoulou, G, Beranger, A, Prud'homme, J-F, Baulac, M, Brice, A, Bruzzone, R, LeGuern, E
• Format: Journal Article
• Language: English
• Published: 01.05.2001
• Subjects: GABRG gene; generalized epilepsy with febrile seizures plus; nocturnal frontal lobe epilepsy; Xenopus laevis
• ISSN: 1061-4036

Major advances in the identification of genes implicated in idiopathic epilepsy have been made. Generalized epilepsy with febrile seizures plus (GEFS+), benign familial neonatal convulsions and nocturnal frontal lobe epilepsy, three autosomal dominant idiopathic epilepsies, result from mutations affecting voltage-gated sodium and potassium channels, and nicotinic acetylcholine receptors, respectively. Disruption of GABAergic neurotransmission mediated by gamma -aminobutyric acid (GABA) has been implicated in epilepsy for many decades. We now report a K289M mutation in the GABA sub(A) receptor 2-subunit gene (GABRG2) that segregates in a family with a phenotype closely related to GEFS+, an autosomal dominant disorder associating febrile seizures and generalized epilepsy previously linked to mutations in sodium channel genes. The K289M mutation affects a highly conserved residue located in the extracellular loop between transmembrane segments M2 and M3. Analysis of the mutated and wild-type alleles in Xenopus laevis oocytes confirmed the predicted effect of the mutation, a decrease in the amplitude of GABA-activated currents. We thus provide the first genetic evidence that a GABA sub(A) receptor is directly involved in human idiopathic epilepsy.