Mutational analysis of GABRG2 in a Japanese cohort with childhood epilepsies

A few mutations in the gene encoding the gamma 2 subunit of the gamma-aminobutyric acid receptor type A (GABRG2) havebeen reported in various types of epilepsy. The aim of this study is to investigate the role of GABRG2 in the pathogenesis ofchildhood epilepsy in a large Japanese cohort. Genetic analysis of GABRG2 was performed on 140 Japanese patients withvarious childhood epilepsies largely including Dravet syndrome and genetic epilepsy with febrile seizures plus. The mutationalanalysis identified one novel missense mutation of GABRG2 (c.236A4G: p.N40S) in a patient with generalized tonic-clonicseizures (GTCS). The mutation was heterozygous and replacing a highly conserved Asn residue with a Ser. The affected aminoacid was located at residue 40 of the mature GABRG2 protein, which was near the first one of two high-affinity benzodiazepine-binding domains of the c2 subunit (Lys-41-Trp-82). This mutation in such an important position may hamper the function of thechannel and contribute to the case’s pathogenesis of GTCS.Journal of Human Genetics (2010) 55, 375–378; doi:10.1038/jhg.2010.47; published online 20 May 2010Keywords: epilepsy; GABRG2; genetics; mutationINTRODUCTIONEpilepsy is a group of heterogeneous disorders characterized byparoxysms resulting from bioelectric hyperexcitation of neuronalnetworks of the brain. Recently, it has been well recognized thatdysfunctions of ion channels expressed in the brain contribute to suchhyperexcitation and hence closely associate with the pathogenesis ofepilepsy. Accordingly, to date, a number of mutations of the genesencoding ion channels have been identified in various types ofepilepsy.Gamma-aminobutyric acid receptor type A (GABA