First genetic evidence of GABAA receptor dysfunction in epilepsy: a mutation in the γ2-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.

Gender-specific contribution of the GABAA subunit genes on 5q33 in methamphetamine use disorder

“…Nevertheless, this should be interpreted with caution as such difference may be caused by biased sampling or simply, a matter of chance. It is worth noting that only one study of alcohol dependence found an association with an SNP conferring aminoacid changes at the GABA A subunit genes on 5q33, 20 while the rest reported associations with SNPs conferring no amino-acid changes; [17][18][19] we found the reported SNPs conferring amino-acid changes [21][22][23][24] not polymorphic in this study. To further this research, additional SNPs should be identified within this gene cluster and these should be combined using haplotype analysis.…”

“…We examined 11 single-nucleotide polymorphisms (SNPs) located across the GABA A subunit gene cluster on 5q33, including eight previously reported, [17][18][19][20][21][22][23][24] two extracted from the dbSNP of National Center for Biotechnology Information and one found in the 5 0 -untranslated region (5 0 -UTR) of the GABA A g2 subunit gene.…”

Mutational analysis of GABRG2 in a Japanese cohort with childhood epilepsies

“…12,13 Up to date, at least seven mutations of GABRG2 including missense mutations, nonsense mutations and splice-site mutation have been associated with a broad spectrum of epilepsies. 1,[4][5][6][7][8]14 The N40S mutation identified in this study affects a highly conserved Asn at residue 40 of the mature g2 subunit, thus, the mutation is adjacent to the first one of the two high-affinity benzodiazepine-binding domains of the g2 subunit (Lys-41-Trp-82 in the mature g2 subunit). Wallace et al 15 had suggested that R43Q mutation in the benzodiazepine-binding site can attenuate benzodiazepine sensitivity of GABA A receptor.…”

“…[1][2][3][4] A mutation of GABRA1 was found in autosomal dominant juvenile myoclonic epilepsy, a rare inherited idiopathic epilepsy phenotype. 2 Several variants of GABRD were not reported as causes of epilepsy but suggested to associate with susceptibility to genetic epilepsy with febrile seizures plus (GEFS+).…”

“…3 In contrast, mutations in GABRG2 have been reported as causes of a wide spectrum of epilepsies, from Dravet syndrome to milder conditions such as childhood absence epilepsy, GEFS+ and FS+. 1,[4][5][6][7][8] Although major progress has been made in tying GABRG2 to some categories of epilepsy (that is, GEFS+, childhood absence epilepsy and Dravet syndrome), its role in most kinds of childhood epilepsy such as benign epilepsy of childhood with centrotemporal spikes, generalized tonic-clonic seizures (GTCS), partial epilepsy and so on remains poorly understood. Accordingly, this study further investigates the role of GABRG2 in the pathogenesis of childhood epilepsy.…”