SODIUM CHANNEL REGULATION AND DISEASE

描述（由申请人提供）：癫痫是一种异常神经元兴奋性的常见疾病，对健康、智力和社会发育具有长期影响。许多抗癫痫药物具有不良的副作用，并且仅针对癫痫的症状，导致无效的癫痫控制。我们的长期目标是通过更好地了解影响神经元兴奋性的因素来促进更有效的癫痫治疗的发展。电压门控钠通道基因SCN 1A（神经元兴奋性的关键调节因子）的突变已在两种形式的显性特发性全身性癫痫中发现：全身性癫痫伴热性惊厥+（GEFSP 2）和婴儿严重肌阵挛性癫痫（SMEI）。GEFSP 2的特征在于持续超过6岁的发热性（发热诱导的）癫痫发作和成人癫痫的发展。SMEI是一种严重的、使人衰弱的儿童癫痫，其特征为发热性和无热性惊厥、智力迟钝和共济失调。在SMEI患者中已发现许多功能丧失的SCN 1A突变，表明SCN 1A表达水平与神经元兴奋性之间存在重要关系。我们推测，关键的SCN 1A调控元件的序列变异也可能导致表达改变，并代表一个重要的，但尚未探索，严重的儿童癫痫的组成部分。我们将通过在患者和未受影响的对照中鉴定的SCN 1A启动子变体的功能分析来检验这一假设。通过多物种序列分析，我们在SCN 1A基因中发现了9个进化上保守的非编码序列（长度> 143 bp）。我们假设这些代表了额外的调节元件。这些区域的生物学功能将使用体外测定和通过小鼠中的靶向缺失的组合来检查。为了进一步研究SCN 1A表达与癫痫发作易感性之间的关系，我们将开发一系列具有10-80%内源性Scn 1A表达水平的小鼠品系。这些表达水平将通过将充分表征的Scnla BAG转基因系与可用的杂合Scnla敲除小鼠杂交来产生。这项研究将为SCN 1A的调节和决定神经元兴奋性的机制提供新的临床相关见解。

DESCRIPTION (provided by applicant): Epilepsy is a common disorder of aberrant neuronal excitability that has long-term consequences for health and intellectual and social development. Many antiepileptic medications have undesirable side effects and only target the symptoms of epilepsy leading to ineffective seizure control. Our long-term goal is to facilitate the development of more effective epilepsy treatments through a better understanding of the factors that affect neuronal excitability. Mutations in the voltage-gated sodium channel gene SCN1A, a critical regulator of neuronal excitability, have been identified in two forms of dominant idiopathic generalized epilepsy: Generalized Epilepsy with Febrile Seizures Plus (GEFSP2) and Severe Myoclonic Epilepsy of Infancy (SMEI). GEFSP2 is characterized by febrile (fever induced) seizures that persist beyond the age of six and the development of adult epilepsy. SMEI is a severe, debilitating childhood epilepsy characterized by febrile and afebrile seizures, mental retardation and ataxia. Many loss-of-function SCN1A mutations have been identified in SMEI patients, suggesting an important relationship between SCN1A expression levels and neuronal excitability. We hypothesize that sequence variation in critical SCN1A regulatory elements can also lead to altered expression and represent an important, but as yet unexplored, component of severe childhood epilepsies. We will test this hypothesis by functional analysis of SCN1A promoter variants identified in patients and in unaffected controls. By multi-species sequence analysis, we have identified 9 evolutionarily conserved non-coding sequences (> 143 bp in length) in the SCN1A gene. We hypothesize that these represent additional regulatory elements. The biological functions of these regions will be examined using a combination of in vitro assays and by targeted deletion in the mouse. To further investigate the relationship between SCN1A expression and seizure susceptibility, we will develop a series of mouse lines with 10-80% of endogenous Scnla expression levels. These expression levels will be generated by crossing well-characterized Scnla BAG transgenic lines to available heterozygous Scnla knock-out mice. This study will provide new, clinically relevant insights into the regulation of SCN1A and the mechanisms that determine neuronal excitability.