The Epilepsy of Infancy With Migrating Focal Seizures: Identification of de novo Mutations of the KCNT2 Gene That Exert Inhibitory Effects on the Corresponding Heteromeric KNa1.1/KNa1.2 Potassium Channel
The Epilepsy of Infancy With Migrating Focal Seizures: Identification of de novo Mutations of the KCNT2 Gene That Exert Inhibitory Effects on the Corresponding Heteromeric KNa1.1/KNa1.2 Potassium Channel
复制标题
伴有迁移性局灶性发作的婴儿期癫痫：KCNT2 基因从头突变的鉴定，该突变对相应的异聚体 KNa1.1/KNa1.2 钾通道产生抑制作用
DOI：
10.3389/fncel.2020.00001
复制
发表时间：
2020-01-24
影响因子：
5.3
通讯作者：
Aniksztejn, Laurent
中科院分区：
文献类型：
--
作者：
Mao, Xiao;Bruneau, Nadine;Aniksztejn, Laurent
婴儿期癫痫伴移行性局灶性发作（EIMFS;以前称为婴儿期恶性移行性部分性发作）是早发性癫痫性脑病（EOEE），其与多灶性发作放电和深度精神发育迟滞相关。EIMFS具有遗传起源，主要由KCNT 1基因中的从头突变引起，而KCNT 2基因中的突变则更罕见。KCNT 1和KCNT 2分别编码钠依赖性电压门控钾通道KNa的KNa1.1（Slack）和KNa1.2（Slick）亚基。相应的突变体同源通道在体外的功能分析表明获得功能的影响。在这里，我们报告了两个新的，从头截断突变KCNT 2：一个突变是移码（p.L48Qfs43），位于N-末端结构域，并在EOEE（可能EIMFS）患者中发现;另一个突变是无义（p.K564*），位于C-末端区域，并在典型的EIMFS患者中发现。使用全细胞膜片钳记录，我们分析了这两个新的KCNT 2突变的功能后果，在转染的中国仓鼠卵巢（CHO）细胞重建KNa1.2同源和KNa1.1/KNa1.2异源通道。我们报告说，这两种突变对KNa功能有显著影响;值得注意的是，它们使异聚体通道的总电流密度降低了~25%（p.K564*）和~55%（p.L48Qfs43）。总的来说，我们的数据强调了KCNT 2参与EOEE，并提供了新的见解异聚KNa通道的作用，在严重的KCNT 2相关的癫痫表型。这可能对未来治疗的制定产生重要影响。
The epilepsy of infancy with migrating focal seizures (EIMFS; previously called Malignant migrating partial seizures of infancy) are early-onset epileptic encephalopathies (EOEE) that associate multifocal ictal discharges and profound psychomotor retardation. EIMFS have a genetic origin and are mostly caused by de novo mutations in the KCNT1 gene, and much more rarely in the KCNT2 gene. KCNT1 and KCNT2 respectively encode the KNa1.1 (Slack) and KNa1.2 (Slick) subunits of the sodium-dependent voltage-gated potassium channel KNa. Functional analyses of the corresponding mutant homomeric channels in vitro suggested gain-of-function effects. Here, we report two novel, de novo truncating mutations of KCNT2: one mutation is frameshift (p.L48Qfs43), is situated in the N-terminal domain, and was found in a patient with EOEE (possibly EIMFS); the other mutation is nonsense (p.K564*), is located in the C-terminal region, and was found in a typical EIMFS patient. Using whole-cell patch-clamp recordings, we have analyzed the functional consequences of those two novel KCNT2 mutations on reconstituted KNa1.2 homomeric and KNa1.1/KNa1.2 heteromeric channels in transfected chinese hamster ovary (CHO) cells. We report that both mutations significantly impacted on KNa function; notably, they decreased the global current density of heteromeric channels by ~25% (p.K564*) and ~55% (p.L48Qfs43). Overall our data emphasize the involvement of KCNT2 in EOEE and provide novel insights into the role of heteromeric KNa channel in the severe KCNT2-related epileptic phenotypes. This may have important implications regarding the elaboration of future treatment.