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疾病，在美国大约有300万人受到影响。大约30%-40%的患者无法用现有的治疗方法实现充分的癫痫控制。了解顽固性癫痫的原因可能会提出替代的治疗策略，以解决这一关键的未得到满足的需求。在大约70%的病例中，癫痫被认为有遗传基础。许多与癫痫相关的基因已经被发现，其中大多数是神经元信号的组成部分，包括离子通道、离子通道相关蛋白和突触蛋白。癫痫脑病是一种特别严重的儿童癫痫，通常包括难治性癫痫发作，并经常可归因于从头开始的单基因突变。通过对小鼠癫痫模型的研究，加深了对癫痫病因和发病机制的认识。在之前的资助期间，我们使用具有电压门控钠通道突变的小鼠模型来检查基因组变异对癫痫严重程度的影响，并确定了几个修饰基因和基因。一些基因影响Scn2aQ54小鼠模型的表型严重性，包括Kcnv2、HLF和Cacna1g。Kcnv2编码Kv8.2电压门控钾通道亚基，它通过与Kcnb1编码的Kv2.1在异构体通道中共同组装来调制延迟整流钾电流。延迟整流钾电流是神经元兴奋性的重要中介，尤其是在重复放电条件下。我们假设KCNV2或KCNB1的基因变异可能与人类癫痫风险有关。最近，我们发现KCNB1的新突变是一种新的原因，它是一种新的原因，早期婴儿癫痫脑病26型(EIEE26)，其特征是药物抵抗癫痫发作并相关的认知和运动障碍。我们建议继续我们关于癫痫遗传基础的研究计划，重点放在这种新描述的综合征EIEE26上。首先，我们将对一大系列KCNB1患者突变进行功能研究，以确定功能缺陷的范围，并确定基因-表型关系。此外，我们还将开发和鉴定EIEE26小鼠模型，以便更好地了解KCNB1突变是如何导致癫痫的。最后，我们将确定基因组背景如何影响Kcnb1小鼠模型的疾病严重性，并确定修饰基因座。拟议的研究将提供对癫痫的遗传结构的洞察，并通过提高分子诊断的精确度和为治疗干预提供新的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.