Characterization of two de novo KCNT1 mutations in children with malignant migrating partial seizures in infancy
Characterization of two de novo KCNT1 mutations in children with malignant migrating partial seizures in infancy
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DOI：
10.1016/j.mcn.2016.01.004
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发表时间：
2016-04-01
影响因子：
3.5
通讯作者：
Weisz, Alessandro
中科院分区：
文献类型：
--
作者：
Rizzo, Francesca;Ambrosino, Paolo;Weisz, Alessandro
KCNT1基因编码Na+激活的K+电流(K-Na)亚基，在多种细胞类型中都有表达。KCNT1基因突变在多种早发性癫痫患者中被发现，包括婴儿期恶性迁移性部分癫痫(MMPSI)，一种严重的早发性癫痫脑病，其特征是耐药灶性癫痫从一个脑区或大脑半球迁移到另一个脑区或大脑半球，以及神经发育停滞或退化，导致严重残疾。在本研究中，我们报告了在两个无关的MMPSI先证者中通过全外显子测序(WES)鉴定出两个新生的杂合子KCNT1突变(G288S和M516V)。异源表达系统的功能研究表明，与野生型KCNT1通道相比，突变KCNT1亚基形成的通道携带更大的电流，无论是作为后者的同源异构体还是异构体。这两个突变都导致了同源通道激活门控的显著左移。有趣的是，KCNT1阻断剂奎尼丁(3-1000 mU M)和苯丙地尔(0.03-10 mU M)以浓度依赖的方式抑制野生型和突变型KCNT1电流，突变型通道对阻断表现出更高的敏感性。后者的结果提示了两种针对不同基因型的药理学策略，以特异性地中和MMPSI患者中KCNT1激活突变的功能障碍。(C)爱思唯尔公司出版的2016年。
The KCNT1 gene encodes for subunits contributing to the Na+-activated K+ current (K-Na), expressed in many cell types. Mutations in KCNT1 have been found in patients affected with a wide spectrum of early-onset epilepsies, including Malignant Migrating Partial Seizures in Infancy (MMPSI), a severe early-onset epileptic encephalopathy characterized by pharmacoresistant focal seizures migrating from one brain region or hemisphere to another and neurodevelopment arrest or regression, resulting in profound disability. In the present study we report identification by whole exome sequencing (WES) of two de novo, heterozygous KCNT1 mutations (G288S and, not previously reported, M516V) in two unrelated MMPSI probands. Functional studies in a heterologous expression system revealed that channels formed by mutant KCNT1 subunits carried larger currents when compared to wild type KCNT1 channels, both as homo- and heteromers with these last. Both mutations induced a marked leftward shift in homomeric channel activation gating. Interestingly, the KCNT1 blockers quinidine (3-1000 mu M) and bepridil (0.03-10 mu M) inhibited both wild-type and mutant KCNT1 currents in a concentration-dependent manner, with mutant channels showing higher sensitivity to blockade. This latter result suggests two genotype tailored pharmacological strategies to specifically counteract the dysfunction of KCNT1 activating mutations in MMPSI patients. (C) 2016 Published by Elsevier Inc.