A mouse model of human idiopathic generalized epilepsy

描述（由申请人提供）：特发性全身性癫痫（IGE）包括几种综合征，其特征为年龄相关的、复发性的和无诱因的全身性癫痫发作，且无可检测的脑病变或代谢异常。最常见的IGE亚型是儿童失神癫痫（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）。IGE的病因是由遗传决定的，迄今为止已经鉴定了大约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，并且IGE的大部分遗传贡献仍未确定，这对开发更有效的治疗方法构成了瓶颈。拷贝数变异（CNVs）最近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，至少有四个CNV已确定在常见的IGE亚型的患者。事实上，人类染色体15q11.2和15q13.3上的微缺失估计占IGE的1%，使这些成为迄今为止确定的IGE的最常见原因。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。本R 03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。小鼠胚胎干细胞（ES）中的同源重组将用于在小鼠7号染色体上的同线间隔侧翼引入loxP位点。Cre重组酶介导的靶间隔的缺失将重演人类缺失事件。除了提供研究这些重要癫痫易感基因位点的机制的机会外，突变小鼠还将有助于更好地了解遗传复杂的临床挑战性疾病，如自闭症和精神分裂症。我们将通过评价癫痫发作阈值和自发性癫痫发作频率来表征小鼠的癫痫发作表型。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。 公共卫生相关性：已知基因突变在特发性全身性癫痫（IGE）的病因学中起重要作用;然而，目前大多数鉴定的癫痫基因导致罕见形式的癫痫，而负责常见形式的IGE的基因在很大程度上仍然未知。去年，估计约1%的常见IGE病例与人类染色体15q11.2和15q13.3的缺失有关。为了了解这些缺失导致癫痫发作的机制，我们将生成并表征携带与患者中观察到的相同缺失的小鼠品系。

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.