A mouse model of human idiopathic generalized epilepsy

描述(申请人提供)：特发性全身性癫痫(IGES)包括几种综合征，其特征是年龄相关、反复发作和无缘无故的全身性癫痫发作，没有可检测到的脑部病变或代谢异常。最常见的免疫球蛋白E亚型为儿童失神癫痫(CAE)、青少年失神癫痫(JAE)、青少年肌阵挛癫痫(JME)和癫痫伴全身强直阵挛发作(EGTCS)。免疫球蛋白E的病因是由遗传学确定的，到目前为止，大约有18个免疫球蛋白E基因被鉴定出来。然而，这些基因是罕见的孟德尔型显性癫痫的罪魁祸首，对IGES的大多数遗传贡献仍未确定，这给更有效的治疗方法的开发带来了瓶颈。近年来，拷贝数变异(CNV)已成为良性和致病遗传变异的重要来源。在过去的一年里，在具有常见的免疫球蛋白E亚型的患者中至少发现了四种CNV。事实上，人类染色体15q11.2和15q13.3上的微缺失估计占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，这些缺失也在自闭症谱系障碍、精神分裂症和智力残疾中被发现，这表明了一种共同的、但尚未确定的机制。这个R03提案的目标是产生和表征人类15q11.2和15q13.3缺失的小鼠模型。小鼠胚胎干细胞(ES)的同源重组将被用来在小鼠7号染色体上的共线区间两侧引入loxP位点。Cre重组酶介导的靶区间的缺失将概括人类的缺失事件。除了提供研究这些重要癫痫易感基因座机制的机会外，突变小鼠还将有助于更好地了解自闭症和精神分裂症等遗传复杂、具有临床挑战性的疾病。我们将通过评估发作阈值和自发发作频率来表征小鼠的癫痫表型。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。 公共卫生相关性：已知基因突变在特发性全身性癫痫(IGES)的病因学中起重要作用；然而，目前发现的大多数癫痫基因与罕见形式的癫痫有关，而导致常见形式的IGE的基因在很大程度上仍不清楚。在过去的一年里，人类染色体15q11.2和15q13.3的缺失被估计为大约1%的常见IGE病例的原因。为了了解这些缺失导致癫痫发作的机制，我们将产生并鉴定携带与在患者中观察到的相同缺失的小鼠系。

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.