Ion channelopathies co-expressed in heart and brain

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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.