不明原因婴儿痉挛症候选易感/致病基因CLCN6的致病机制研究

婴儿痉挛症（Infantile Spasms, ISs）是婴儿期最常见的一种癫痫脑病，也是癫痫中症状最重、预后最差、对社会和家庭影响最大的表型之一。新近研究证实遗传因素是不明原因ISs的重要病因。基于申请团队前期研究基础，结合最新进展，认为CLCN6可能是ISs的新易感/致病基因。本研究拟在此类患儿中进行群体验证分析，明确CLCN6基因突变在ISs患者中的发生率及基因型-表型关系。同时采用CRISPR/Cas9靶向基因编辑技术建立携带突变的小鼠，NMDA诱导建立小鼠ISs模型，结合离体脑片培养、膜片钳等技术，从在体-细胞-分子水平探讨CLCN6基因突变对氯离子通道功能、神经元兴奋性和ISs易感/致病性的影响。其研究成果不仅可能在国际上首次证实CLCN6为ISs新的易感/致病基因，扩展我们对ISs发病机制的认识；同时可通过本研究项目建立成熟、规范的ISs疾病数据库，生物标本库和基因诊断平台。

Infantile spasms (ISs) is one of the most severe epileptic encephalopathy with the worst prognosis in childhood. Recent studies showed that genetic factors may play most important role. Based on our previous study and the newest development, CLCN6 is expected as a novel candidate gene associated with ISs. This study plans to detect the mutations of the coding exons and intron-exon junction regions of CLCN6 gene among unexplained ISs patients to identify the incidence and genotype-phenotype correlation in these patients. CRISPR/Cas9 targeted gene editing, plasmid transfection and patch clamp are used to explore the influence of CLCN6 gene mutation on ISs susceptibility and neuron excitability. The study could firstly illustrate CLCN6 as a novel candidate gene associated with ISs, enriching our understanding of the pathological mechanism of ISs, providing new precise target of treatment and establishing a mature and standardized ISs database, biological specimen banks and genetic diagnosis platform.