GABRB2基因突变导致癫痫的基因型和表型相关性及发病机制研究

GABAA受体基因突变可导致遗传性癫痫，部分可表现为癫痫性脑病，起病年龄早，伴有发育落后，且对抗癫痫药物疗效差，预后不良。GABAA受体相关基因包括GABRA1、GABRB2、GABRB3等19种亚型，多数基因突变致病机制不明确。本课题组已收集GABAA受体相关基因导致的癫痫共71例，在其中15例GABRB2突变患儿中，发现12例携带国际上未报道的新突变，表型可为轻的热性惊厥到严重的癫痫性脑病，其中Dravet综合征、遗传性癫痫伴热性惊厥附加症和热性惊厥为国际上未报道的新表型，少数表型严重的患儿可导致死亡。本研究将对新发现的GABRB2基因突变构建突变体，应用生物信息技术进行结构建模，并采用膜片钳、蛋白印迹等方法从细胞水平、组织水平和小鼠模型进行功能研究，明确GABRB2突变导致癫痫和发育落后的发病机制及突变所在不同区域导致癫痫表型轻重不一的机制，为癫痫的精准治疗提供新的思路。

The mutation in genes encoding GABAA receptors can lead to genetic epilepsy, some of which can be characterized by epileptic encephalopathy with early onset, development delay, antiepileptic drug resistance and poor prognosis. GABAA receptor-related genes include 19 subtypes such as GABRA1, GABRB2 and GABRB3. The pathogenesis of most gene mutations is still unclear. A total of 71 cases of epilepsy caused by GABAA receptor related genes have been collected in our epilepsy research group. In the 15 children with GABRB2 mutations, 12 were novel mutations. Phenotypes ranged from mild febrile seizures to severe epileptic encephalopathy. Dravet syndrome, genetic epilepsy with febrile seizures plus and febrile seizures were observed as new phenotypes of GABRB2 mutations. Few children with severe phenotype may deceased. In this study, we will perform functional study of GABRB2 mutation sites, from cell level, tissue level and mouse model. We construct mutants for newly discovered mutations, apply bioinformatics technology for structural modeling, and use patch clamp, Western blotting and other methods. Performing functional studies to clarify the pathogenesis of GABRB2 mutations that cause epilepsy and development delay, and the mechanisms by which the mutations in different regions cause different epileptic phenotypes. This study can provide new ideas for the accurate treatment of epilepsy.