Combined Approach to the Genetic Basis of Epilepsy

 描述（由申请人提供） 癫痫是一种常见的神经系统疾病，在美国影响大约300万人。大约30-40%的患者无法通过目前可用的治疗实现充分的癫痫控制。了解难治性癫痫的原因可能会提出替代治疗策略，以解决这一关键的未满足的需求。据推测，癫痫在大约70%的病例中具有遗传基础。许多与癫痫相关的基因已经被鉴定，并且大多数是神经元信号传导的组分，包括离子通道、离子通道相关蛋白和突触蛋白。癫痫性脑病是特别严重的儿童癫痫，通常包括顽固性癫痫发作，并且通常归因于从头单基因突变。小鼠癫痫模型的研究增加了我们对癫痫病因和发病机制的认识。在上一个资助期，我们使用电压门控钠通道突变的小鼠模型来研究基因组变异对癫痫严重程度的影响，并确定了几个修饰位点和基因。许多基因影响Scn 2aQ 54小鼠模型的表型严重程度，包括Kcnv 2、Hlf和Cacna 1g。Kcnv 2编码Kv8.2电压门控钾通道亚基，其通过在异聚体通道中与由Kcnb 1编码的Kv2.1共组装来调节延迟整流钾电流。延迟整流钾电流是神经元兴奋性的重要介质，特别是在重复放电条件下。我们假设KCNV 2或KCNB 1的遗传变异可能导致人类癫痫风险。最近，我们确定了KCNB 1的从头突变作为一种新的原因早期婴儿癫痫性脑病26型（EIEE 26），其特征是耐药性癫痫发作与相关的认知和运动缺陷。我们建议继续我们的研究计划，对癫痫的遗传基础，重点是这种新描述的综合征，EIEE 26。首先，我们将对大量KCNB 1患者突变进行功能研究，以确定功能缺陷的范围并定义基因型-表型关系。此外，我们将开发和表征EIEE 26的小鼠模型，以更好地了解KCNB 1突变如何导致癫痫。最后，我们将确定基因组背景如何影响Kcnb 1小鼠模型的疾病严重程度，并确定修饰基因座。拟议的研究将深入了解癫痫的遗传结构，并通过提高分子诊断的精确度和提出治疗干预的新途径来改善患者的治疗。

 DESCRIPTION (provided by applicant) Epilepsy is a common neurological disorder that affects approximately three million people in the United States. Approximately 30-40% of patients are unable to achieve adequate seizure control with currently available treatments. Understanding the causes of intractable epilepsy may suggest alternative therapeutic strategies that will address this critical unmet need. Epilepsy is presumed to have a genetic basis in approximately 70% of cases. Numerous genes associated with epilepsy have been identified, and most are components of neuronal signaling, including ion channels, ion channel-associated proteins, and synaptic proteins. Epileptic encephalopathies are particularly severe childhood epilepsies that often include intractable seizures, and are frequently attributable to de novo single gene mutations. Studying mouse models of epilepsy have increased our understanding of the etiology and pathogenesis of epilepsy. In the previous funding period, we used mouse models with voltage-gated sodium channel mutations to examine the effect of genome variation on epilepsy severity and identified several modifier loci and genes. A number of genes influenced phenotype severity of the Scn2aQ54 mouse model, including Kcnv2, Hlf, and Cacna1g. Kcnv2 encodes the Kv8.2 voltage-gated potassium channel subunit, which modulates delayed rectifier potassium currents by co- assembling in heteromeric channels with Kv2.1, encoded by Kcnb1. Delayed rectifier potassium current is an important mediator of neuronal excitability particularly under conditions of repetitive firing. We hypothesized that genetic variation in KCNV2 or KCNB1 may contribute to epilepsy risk in humans. Recently, we identified de novo mutations of KCNB1 as a novel cause early infantile epileptic encephalopathy type 26 (EIEE26), which is characterized by pharmacoresistant seizures with associated cognitive and motor deficits. We propose to continue our research program on the genetic basis of epilepsy with a focus on this newly described syndrome, EIEE26. First, we will perform functional studies on a large series of KCNB1 patient mutations in order to determine the range of functional defects and define genotype-phenotype relationships. In addition, we will develop and characterize murine models of EIEE26 in order to better understand how KCNB1 mutations lead to epilepsy. Finally, we will determine how genome background influences disease severity in Kcnb1 mouse models and identify modifier loci. The proposed studies will provide insight into the genetic architecture of epilepsy, and improve treatment of patients by enhancing precision of molecular diagnosis and suggesting novel pathways for therapeutic intervention.