First genetic evidence of GABAA receptor dysfunction in epilepsy:: a mutation in the γ2-subunit gene
First genetic evidence of GABAA receptor dysfunction in epilepsy:: a mutation in the γ2-subunit gene
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DOI：
10.1038/88254
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发表时间：
2001-05-01
期刊：
影响因子：
30.8
通讯作者：
LeGuern, E
中科院分区：
文献类型：
--
作者：
Baulac, S;Huberfeld, G;LeGuern, E
在鉴定与特发性癫痫有关的基因方面取得了重大进展。全身性癫痫伴热性惊厥加重（GEFS+）、良性家族性新生儿惊厥和夜间额叶癫痫（三种常染色体显性特发性癫痫）分别由影响电压门控钠和钾通道以及烟碱乙酰胆碱受体的突变引起（1-6）。数十年来，γ-氨基丁酸（GABA）介导的GABA能神经传递中断与癫痫有关（7）。我们现在报告了GABA（A）受体γ 2亚基基因（GABRG 2）中的K289 M突变，该突变在一个具有与GEFS+密切相关的表型的家族中分离（参考文献8），GEFS+是一种常染色体显性遗传疾病，与先前与钠通道基因突变相关的热性惊厥和全身性癫痫相关（1，2）。K289 M突变影响位于跨膜片段M2和M3之间的细胞外环中的高度保守残基。在非洲爪蟾卵母细胞的突变和野生型等位基因的分析证实了预测的效果的突变，GABA激活电流的幅度下降。因此，我们提供了第一个遗传学证据，GABA（A）受体直接参与人类特发性癫痫。
Major advances in the identification of genes implicated in idiopathic epilepsy have been made. Generalized epilepsy with febrile seizures plus (GEFS+), benign familiar 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(1-6), Disruption of GABAergic neurotransmission mediated by gamma -aminobutyric acid (GABA) has been implicated in epilepsy for many decades(7). 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(1,2). 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 GABA(A) receptor is directly involved in human idiopathic epilepsy.