Nature Genetics
28, 46 - 48 (2001)
doi:10.1038/ng0501-46
First genetic evidence of GABAA receptor dysfunction in epilepsy: a mutation in the  2-subunit geneStéphanie Baulac1, Gilles Huberfeld1, Isabelle Gourfinkel-An2, 4, Georgia Mitropoulou5, Alexandre Beranger1, Jean-François Prud'homme4, Michel Baulac2, Alexis Brice1, 3, Roberto Bruzzone5
& Eric LeGuern1, 31
INSERM U289, Cytogénétique et Embryologie, Hôpital de la Pitié-Salpêtrière, Paris, France. 2
Centre d'Epileptologie, Cytogénétique et Embryologie, Hôpital de la Pitié-Salpêtrière, Paris, France. 3
Département de Génétique, Cytogénétique et Embryologie, Hôpital de la Pitié-Salpêtrière, Paris, France. 4
Généthon, Evry, France. 5
NRSN, Institut Pasteur, Paris, France.
Correspondence should be addressed to Eric LeGuern leguern@ccr.jussieu.frMajor 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, respectively1,
2,
3,
4,
5,
6. Disruption of GABAergic neurotransmission mediated by  -aminobutyric acid (GABA) has been implicated in epilepsy for many decades7. We now report a K289M mutation in the GABAA receptor 2-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 genes1,
2. 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 GABAA receptor is directly involved in human idiopathic epilepsy.
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