KCNT2基因突变在婴儿癫痫伴游走性局部性发作发病机制中的作用研究

婴儿癫痫伴游走性局部性发作（EIMFS）是一种较为少见的婴儿期癫痫脑病且预后不良，目前EIMFS被认为主要与遗传因素相关且KCNT1基因是EIMFS的主要致病基因。而由于KCNT2与KCNT1在蛋白质序列、结构、功能、表达等方面具有较高的相似度，KCNT2基因极有可能也是EIMFS的致病基因。在前期工作中，我们通过外显子组测序发现两个典型的EIMFS患者各携带了一个位于KCNT2的新生突变，分别为c.1690A>T 、c.143-144 delTA并已成功构建了Kcnt2基因敲除小鼠模型。本研究拟在前期研究的基础上，明确KCNT2的突变对SLICK通道电生理性质的影响及对神经元兴奋性的影响，通过对Kcnt2基因敲除小鼠的分析阐明Kcnt2的缺失对小鼠脑发育的影响，并首次证明KCNT2是EIMFS新的致病基因，为药物治疗EIMFS提供新的依据、思路和视角。

Epilepsy of Infancy with Migrating Focal Seizures（EIMFS）is a relatively rare infantile epileptic encephalopathy with poor prognosis. EIMFS is considered to be mainly associated with genetic factors and KCNT1 gene is the major causative gene of EIMFS.Because KCNT2 and KCNT1 have high similarity in protein sequence, structure, function and expression, the KCNT2 gene is highly likely to be the pathogenic gene of EIMFS. In the previous work, we found two De novo KCNT2 mutations in two typical EIMFS patients through whole exome sequencing, which are c.1690A>T and c.143-144 delTA respectively. And we have successfully constructed a Kcnt2 knock-out mouse model.Based on the previous studies, this study intends to clarify the effects of mutations in KCNT2 on the electrophysiological properties of SLICK channels and the effects on neuronal excitability. The analysis of Kcnt2 knockout mice will also shed light on the hypothesis that the deletion of Kcnt2 affects brain development in mice. It will be proved for the first time in this study that KCNT2 is a new causative gene of EIMFS and provides a new basis, thinking and perspective for drug treatment of EIMFS.