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Nat Genet 2001 May 01;281:46-8. doi: 10.1038/ng0501-46.
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First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene.

Baulac S , Huberfeld G , Gourfinkel-An I , Mitropoulou G , Beranger A , Prud'homme JF , Baulac M , Brice A , Bruzzone R , LeGuern E .

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.

PubMed ID: 11326274
Article link: Nat Genet