Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures.
Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures.
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DOI：
10.1038/ncomms9038
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发表时间：
2015-09-03
影响因子：
16.6
通讯作者：
Kurian MA
中科院分区：
文献类型：
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作者：
Stödberg T;McTague A;Ruiz AJ;Hirata H;Zhen J;Long P;Farabella I;Meyer E;Kawahara A;Vassallo G;Stivaros SM;Bjursell MK;Stranneheim H;Tigerschiöld S;Persson B;Bangash I;Das K;Hughes D;Lesko N;Lundeberg J;Scott RC;Poduri A;Scheffer IE;Smith H;Gissen P;Schorge S;Reith ME;Topf M;Kullmann DM;Harvey RJ;Wedell A;Kurian MA
由SLC 12 A5编码的钾-氯共转运蛋白KCC 2通过维持氯离子的超极化梯度在快速突触抑制中起着重要作用。KCC 2功能障碍与人类癫痫有关，但迄今为止，还没有描述过单基因KCC 2相关的癫痫疾病。在这里，我们显示了隐性功能丧失SLC 12 A5突变的患者患有严重的癫痫发作耐药性癫痫综合征，婴儿癫痫伴迁移性局灶性发作（EIMFS）。KCC 2表面表达减少、蛋白糖基化减少和氯离子排出受损导致KCC 2活性丧失，从而损害正常突触抑制并促进这种早发性癫痫性脑病中的神经元兴奋性。钾-氯共转运蛋白KCC 2是维持神经元中氯离子梯度的重要成分。Stodberg及其同事在这里鉴定了编码基因SLC 12 A5的功能缺失突变，这种突变损害了与早发性癫痫相关的正常突触功能。
The potassium-chloride co-transporter KCC2, encoded by SLC12A5, plays a fundamental role in fast synaptic inhibition by maintaining a hyperpolarizing gradient for chloride ions. KCC2 dysfunction has been implicated in human epilepsy, but to date, no monogenic KCC2-related epilepsy disorders have been described. Here we show recessive loss-of-function SLC12A5 mutations in patients with a severe infantile-onset pharmacoresistant epilepsy syndrome, epilepsy of infancy with migrating focal seizures (EIMFS). Decreased KCC2 surface expression, reduced protein glycosylation and impaired chloride extrusion contribute to loss of KCC2 activity, thereby impairing normal synaptic inhibition and promoting neuronal excitability in this early-onset epileptic encephalopathy. The potassium-chloride co-transporter, KCC2 is an essential component in maintaining a gradient for chloride ions in neurons. Here Stodberg and colleagues identify loss-of-function mutations in the encoding gene SLC12A5, which impair normal synaptic function associated with early-onset epilepsy.