title: First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene.
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 gamma-aminobutyric acid (GABA) has been implicated in epilepsy for many decades. We now report a K289M mutation in the GABA(A) receptor gamma2-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(A) receptor is directly involved in human idiopathic epilepsy.
authors.affiliation: INSERM U289, Cytogénétique et Embryologie, Hôpital de la Pitié-Salpêtrière, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Baulac
authors.forename: G
authors.initials: G
authors.lastname: Huberfeld
authors.forename: I
authors.initials: I
authors.lastname: Gourfinkel-An
authors.forename: G
authors.initials: G
authors.lastname: Mitropoulou
authors.forename: A
authors.initials: A
authors.lastname: Beranger
authors.forename: J F
authors.initials: JF
authors.lastname: Prud'homme
authors.forename: M
authors.initials: M
authors.lastname: Baulac
authors.forename: A
authors.initials: A
authors.lastname: Brice
authors.forename: R
authors.initials: R
authors.lastname: Bruzzone
authors.forename: E
authors.initials: E
authors.lastname: LeGuern
mesh_terms: D000595:Amino Acid Sequence; D020090:Chromosome Segregation; D017124:Conserved Sequence; D004553:Electric Conductivity; D004827:Epilepsy / Q000235:genetics*; D020936:Epilepsy, Benign Neonatal / Q000235:genetics; D017034:Epilepsy, Frontal Lobe / Q000235:genetics; D004829:Epilepsy, Generalized / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D021122:Protein Subunits; D011963:Receptors, GABA-A / Q000235:genetics*; D003294:Seizures, Febrile / Q000235:genetics; D017386:Sequence Homology, Amino Acid
chemical_list: D021122:Protein Subunits; D011963:Receptors, GABA-A