Ion channelopathies co-expressed in heart and brain.

描述（由申请人提供）：神经元的兴奋性和致痫性是由电压和配体门控离子通道的相互作用决定的，离子通道基因的突变现在被认为是独立定义的遗传性癫痫综合征和心律失常的重要原因。最近的证据表明，这些基因的一个子集在心脏和大脑中共同表达。大量的临床和实验证据支持癫痫发作和心律失常共存，许多临床报告提示“致心律失常性癫痫”是癫痫猝死（SUDEP）的病理生理机制。长QT综合征（LQTS）越来越被认为是特发性心律失常和心源性猝死的原因之一。已鉴定出7个LQT位点和6个LQT基因（SCN5A、KvLQT1、HERG、KCNE1、KCNE2、KCNJ2）。突变改变了通道的电生理特性，从而使心脏易发生致命的心律失常。来自我们实验室的研究数据表明，SCN5A在心脏和大脑边缘区域有选择性地共表达，这是一个天生容易发生癫痫的网络。HERG、KCNE2和kcnj2基因在大脑中有表达，但它们尚未被区域定位。本项目将扩展我们的初步数据，证实LQT基因在中枢神经系统的表达，并通过以下方法测试它们在癫痫中的作用：1)利用原位杂交技术定位哺乳动物大脑中已知的LQT基因（KvLQT1, KCNE1， HERG， KCNE2和KCNJ2），以便与神经表型相关；2)分析癫痫心律失常患者（包括SUDEP患者）的基因组DNA，以确定这些基因是否存在突变。

DESCRIPTION (provided by applicant): Neuronal excitability, and thus epileptogenicity, is critically governed by the interaction of voltage-and ligand-gated ion channels and mutations of ion channel genes are now recognized as an important cause of independently defined inherited epilepsy syndromes and cardiac arrhythmias. Recent evidence indicates that a subset of these genes is co-expressed in heart and brain. There is extensive clinical and experimental evidence supporting coexistence of seizures and cardiac arrhythmias, and many clinical reports suggest that "arrhythmogenic epilepsy" is the pathophysiological mechanism of sudden unexplained death in epilepsy (SUDEP). Long QT syndrome (LQTS) has been increasingly recognized as a cause for idiopathic cardiac arrhythmia and sudden cardiac death. Seven LQT loci and six LQT genes (SCN5A, KvLQT1, HERG, KCNE1, KCNE2, KCNJ2) have been identified. Mutations alter electrophysiological properties of a channel thus predisposing the heart towards fatal arrhythmias. Research data originating from our laboratory demonstrated that SCN5A is selectively co-expressed in heart and the brain limbic region, a network inherently prone towards epileptogenesis. HERG, KCNE2 and-KCNJ2 genes are expressed in brain, however they have not yet been regionally localized. This project will extend our preliminary data confirming CNS expression of LQT genes and test their involvement in epilepsy by 1) localizing the known LQT genes (KvLQT1, KCNE1, HERG, KCNE2 and KCNJ2) in mammalian brain using in situ hybridization to permit correlation with neurological phenotypes, 2) analyzing the genomic DNA of epilepsy patient with cardiac arrhythmias, including cases diagnosed as SUDEP, for the presence of mutations in these genes. It is our hypothesis that mutations in ion channel genes co-expressed in heart and brain underlie the clinical phenotype of cardiac arrhythmias and seizures, and may ultimately lead to (SUDEP). During the course of this study we will expand a clinical database of seizure patients with idiopathic epilepsies and utilize it to screen for ion channelopathies. We will analyze the DNA of epilepsy patients with concurrent cardiac history, and the DNA of cases diagnosed as SUDEP. The LQT genes will be studied using PCR, dHPLC, and direct sequencing methods. This research may help to determine the roles that LQT genes may play in the etiology of seizures and SUDEP. It may also assist in defining an epilepsy population at risk for sudden death, which would allow initiation of life-saving preventative measures and the design of gene-specific therapy for the affected patients.