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- Title
First genetic evidence of GABA<sub>A</sub> receptor dysfunction in epilepsy: a mutation in the γ2-subunit gene.
- Authors
Baulac, Stéphanie; Huberfeld, Gilles; Gourfinkel-An, Isabelle; Mitropoulou, Georgia; Beranger, Alexandre; Prud'homme, Jean-François; Baulac, Michel; Brice, Alexis; Bruzzone, Roberto; LeGuern, Eric
- Abstract
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 γ-aminobutyric acid (GABA) has been implicated in epilepsy for many decades. We now report a K289M mutation in the GABA[sub A] receptor γ2-subunit gene (GABRG2) that segregates in a family with a phenotype closely related to GEFS+ (ref. 8), 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.
- Publication
Nature Genetics, 2001, Vol 28, Issue 1, p46
- ISSN
1061-4036
- Publication type
Academic Journal
- DOI
10.1038/ng0501-46