Stödberg Tommy, McTague Amy, Ruiz Arnaud J, Hirata Hiromi, Zhen Juan, Long Philip, Farabella Irene, Meyer Esther, Kawahara Atsuo, Vassallo Grace, Stivaros Stavros M, Bjursell Magnus K, Stranneheim Henrik, Tigerschiöld Stephanie, Persson Bengt, Bangash Iftikhar, Das Krishna, Hughes Deborah, Lesko Nicole, Lundeberg Joakim, Scott Rod C, Poduri Annapurna, Scheffer Ingrid E, Smith Holly, Gissen Paul, Schorge Stephanie, Reith Maarten E A, Topf Maya, Kullmann Dimitri M, Harvey Robert J, Wedell Anna, Kurian Manju A
Department of Women's and Children's Health, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
Neuropediatric Unit, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
Nat Commun. 2015 Sep 3;6:8038. doi: 10.1038/ncomms9038.
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.
由SLC12A5编码的氯化钾共转运体KCC2通过维持氯离子的超极化梯度在快速突触抑制中发挥着重要作用。KCC2功能障碍与人类癫痫有关，但迄今为止，尚未描述与KCC2相关的单基因癫痫疾病。在此，我们展示了患有严重婴儿期起病的药物抵抗性癫痫综合征——婴儿期迁移性局灶性癫痫发作（EIMFS）的患者中存在隐性功能丧失的SLC12A5突变。KCC2表面表达降低、蛋白质糖基化减少以及氯离子外排受损导致KCC2活性丧失，从而损害了这种早发性癫痫性脑病中的正常突触抑制并促进神经元兴奋性。
