A mouse model of human idiopathic generalized epilepsy

描述（由申请人提供）：特发性全身性癫痫（IGEs）包括几种综合征，其特征是在没有可检测到的脑损伤或代谢异常的情况下，与年龄相关，复发性和无因性全身性癫痫发作。最常见的IGE亚型是儿童缺失性癫痫（CAE）、青少年缺失性癫痫（JAE）、青少年肌阵挛性癫痫（JME）和癫痫伴全身性强直-阵挛发作（EGTCS）。IGE的病因是由基因决定的，迄今为止已鉴定出大约18个IGE基因。然而，这些基因是导致罕见的孟德尔显性癫痫的原因，而且大多数对IGEs的遗传贡献仍未确定，这对开发更有效的治疗方法构成了瓶颈。拷贝数变异（CNVs）近年来已成为良性和致病性遗传变异的重要来源。在过去的一年中，在常见IGE亚型患者中至少发现了四种CNVs。事实上，据估计，人类染色体15q11.2和15q13.3上的微缺失占IGE的1%，使它们成为迄今为止发现的最常见的IGE原因。有趣的是，在自闭症谱系障碍、精神分裂症和智力残疾中也发现了这些缺失，这表明存在一种共同的、但尚未确定的机制。本R03提案的目标是生成和表征人类15q11.2和15q13.3缺失的小鼠模型。将利用小鼠胚胎干细胞（ES）的同源重组技术，在小鼠7号染色体的合成间隔两侧引入loxP位点。Cre重组酶介导的靶间隔缺失将重现人类缺失事件。除了为研究这些重要的癫痫易感位点的机制提供机会外，突变小鼠还将有助于更好地理解遗传复杂的、具有临床挑战性的疾病，如自闭症和精神分裂症。我们将通过评估发作阈值和自发发作频率来表征小鼠的发作表型。这些小鼠将为详细的表型分析和机制研究提供独特的资源。

DESCRIPTION (provided by applicant): The idiopathic generalized epilepsies (IGEs) encompass several syndromes that are characterized by age- related, recurrent, and unprovoked generalized seizures in the absence of detectable brain lesions or metabolic abnormalities. The most common IGE subtypes are childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with generalized tonic-clonic seizures (EGTCS). The etiology of IGE is genetically determined, and approximately 18 IGE genes have been identified to date. However, these genes are responsible for rare, Mendelian forms of dominant epilepsy and most of the genetic contributions to the IGEs remain unidentified, presenting a bottleneck to the development of more effective treatments. Copy number variants (CNVs) have recently emerged as an important source of both benign and pathogenic genetic variation. Within the last year, at least four CNVs have been identified in patients with common IGE subtypes. In fact, microdeletions on human chromosome 15q11.2 and 15q13.3 are estimated to account for 1% of IGE, making these the most common causes of IGE identified to date. Interestingly, these deletions have also been identified in autism spectrum disorders, schizophrenia and intellectual disability, suggesting a shared, but yet unidentified mechanism. The goal of this R03 proposal is to generate and characterize mouse models of the human 15q11.2 and 15q13.3 deletions. Homologous recombination in mouse embryonic stem cells (ES) will be used to introduce loxP sites flanking the syntenic intervals on mouse chromosome 7. Cre recombinase mediated deletion of the target intervals will recapitulate the human deletion event. In addition to providing the opportunity to study the mechanisms of these important epilepsy susceptibility loci, the mutant mice will also facilitate a better understanding of genetically complex, clinically challenging disorders such as autism and schizophrenia. We will characterize the seizure phenotype of the mice by evaluating seizure thresholds and spontaneous seizure frequency. These mice will provide a unique resource for detailed phenotypic analysis and mechanistic studies. PUBLIC HEALTH RELEVANCE: Genetic mutations are known to play an important role in the etiology of the idiopathic generalized epilepsies (IGEs); however, most currently identified epilepsy genes contribute to rare forms of epilepsy, and the genes responsible for common forms of IGE remain largely unknown. Within the last year, deletions on human chromosome 15q11.2 and 15q13.3 were estimated to be responsible for approximately 1% of cases of common IGE. In order to understand the mechanism by which these deletions lead to seizure generation, we will generate and characterize mouse lines that carry the same deletions that were observed in the patients.