新的特发性癫痫综合征致病基因的克隆与功能研究

Idiopathic epilepsy syndromes (IES) caused by genetic factors count for 40% of epilepsies, the second most common neurological disorders. However, the majority of the genetic burden in the IES remains unsolved. In the previous study, we found four large pedigrees of Chinese origin affected with IES. Three pedigrees' clinical phenotype is not yet reported in publications nor recognized by Commission on Classification and Terminology of the International League Against Epilepsy (ILAE), indicating the phenotype is the most likely to be one new IES, which we temporarily named as X idiopathic epilepsy syndrome (XIES) in this study. The other one is affected with epilepsy with generalized tonic-clonic seizures only (EGTCSA). Causative genes of four IES pedigrees are not mapped or cloned yet. Known causative genes and loci frequently involved in other IES are excluded from our four pedigrees, indicating the four pedigrees are most likely harboring novel causative gene(s). Exome sequencing was completed for pedigree with EGTCSA and data analysis initially directed to sixteen candidate genes. Based on the previous studies, we will expand IES pedigrees collecting. Combined with mapping by SNP linkage beadchip, exome sequencing will be applied to identify causative gene(s) of XIES and EGTCSA. Follow-up functional studies on the identified causative gene(s) will be performed. The corresponding findings are hoped to provide substantial rationale and breakthrough for molecular pathogenesis elucidation, diagnosis and treatment of IES, while to propose new epilepsy syndrome(s).

癫痫是最常见的第二大类神经系统疾病，由遗传因素所致的特发性癫痫综合征（IES）在癫痫中占近40%，但目前大部分IES的致病基因仍未克隆明确。前期工作中，我们收集到4个中国汉族人群IES大家系，其中3个家系临床表型尚未见报道并纳入ILAE分类方案，极可能代表一种新的特发性癫痫综合征，我们暂命名为X特发性癫痫综合征（XIES），1个家系为仅有全面性强直阵挛性发作的癫痫（EGTCSA），目前致病基因均尚未定位和克隆。我们前期工作对4个家系完成的检测，提示极可能存在新的致病基因；EGTCSA家系已完成外显子组测序和数据分析，初步锁定16个候选基因。本研究将继续扩大全国范围内IES家系收集，运用外显子组测序结合SNP微珠芯片连锁分析定位，克隆XIES和EGTCSA致病基因，进行致病基因功能初步研究，以期为探索IES分子发病机制、诊断、治疗，提供理论依据和寻求突破性进展，并可能由此命名新的癫痫综合征。

由遗传因素所致的特发性癫痫综合征（IES）的致病基因大部分尚未克隆明确。本项目研究以IES大家系为主要研究对象，运用全基因外显子组测序结合SNP微珠芯片连锁分析定位，进行了致病基因的定位、克隆，并对克隆的致病基因功能进行初步研究。我们成功的在IES家系1中定位并克隆致病基因X，并发现其突变可能影响中枢神经元信号通路而导致癫痫，此重要研究结果，将成为除了电压/配体门控离子通道异常之外，一种全新的癫痫发病机制揭示。IES家系2-4已完成的基因检测，未能发现与家系共分离的致病性碱基变异。在另外新收集的1个IES大家系中成功定位并克隆新的致病基因K，其突变可能改变神经元电活动稳定性而致病。本项目研究所取得的突破性进展，将对IES的分子发病机制阐释、分类、诊断、精准治疗提供理论依据并产生深远影响。