Complex genetic interactions in mouse model of sudden death in epilepsy (SUDEP)

描述（由申请人提供）：这项工作的总体目标是研究癫痫猝死（SUDEP）背景下Kcna1和Scn2a离子通道基因突变之间的基因相互作用。癫痫患者因未知病理原因突然死亡的可能性是一般人群的24倍；这些死亡被归类为猝死症，是癫痫相关死亡的主要原因。有几个基因与SUDEP有关，但其遗传病因在很大程度上是未知的，可能涉及多个易感基因变异的共同遗传。这个提议

DESCRIPTION (provided by applicant): The overall goal of this work is to examine digenic interactions between mutations in the Kcna1 and Scn2a ion channel genes in the context of sudden unexpected death in epilepsy (SUDEP). People with epilepsy are 24 times more likely than the general population to die suddenly for unknown pathological reasons; these deaths are classified as SUDEP and represent the leading cause of epilepsy-related mortality. Several genes have been linked anecdotally to SUDEP, but its genetic etiology is largely unknown and likely complex involving the co-inheritance of multiple susceptibility gene variants. This proposal investigates the ability of subclinical Scn2a-null heterozygosity to act as a protective genetic modifier of epilepsy and premature death in the Kcna1 knockout mouse model of SUDEP. Scn2a, a human epilepsy gene, encodes Nav1.2 voltage-gated sodium channel Alpha-subunits but the knockout mutation utilized here has not been found to cause epilepsy. Kcna1, also a human epilepsy gene, encodes Kv1.1 voltage-gated potassium channel Alpha-subunits that normally act to dampen neuronal excitability. Kcna1 knockout mice accurately model human SUDEP by exhibiting severe epilepsy, brain-driven cardiac dysfunction, and premature death. Given the expression overlap and mutually opposing excitability effects of the two genes, the proposed research tests the hypothesis that subclinical Scn2a-null heterozygosity reduces SUDEP incidence in Kcna1-null mice by suppressing neurocardiac dysfunction and neuronal hyperexcitability associated with the absence of Kv1.1 channels. Preliminary data shows that Scn2a-null heterozygosity prevents SUDEP in Kcna1 knockouts increasing their survival threefold. In Aim 1, video electroencephalography-electrocardiography (EEG-ECG) is used to determine whether Scn2a-null heterozygosity reduces epileptiform discharges and/or cardiac abnormalities in Kcna1-null mice. Aim 2 seeks to identify neuronal networks exhibiting functional interaction between Scn2a and Kcna1 by analyzing changes in expression of molecular biomarkers associated with abnormal neuronal activation, such as c-Fos. This research utilizes a novel digenic mouse model as an important first step towards understanding the complex genetic interactions underlying SUDEP with the ultimate goal of improving genotype-based risk prediction, prevention, and therapy in epilepsy. The ability of Scn2a-null heterozygosity to suppress the Kcna1 SUDEP phenotype would demonstrate a proof-of-principle that even subclinical gene variants without obvious phenotypes must be considered when evaluating the genetic risk profiles of epilepsy patients since those alleles can also be critical modifiers of disease susceptibility. Furthermore, the examination of molecular biomarker endophenotypes in this digenic model has the potential to identify previously unrecognized brain networks that are important for SUDEP pathophysiology and candidate therapeutic targets for future studies.