Department of Pharmacology and Medicine, Vanderbilt University, Nashville, TN 37232-0275, USA.
Proc Natl Acad Sci U S A. 2011 Mar 29;108(13):5443-8. doi: 10.1073/pnas.1017539108. Epub 2011 Mar 14.
Mutations in voltage-gated ion channels are responsible for several types of epilepsy. Genetic epilepsies often exhibit variable severity in individuals with the same mutation, which may be due to variation in genetic modifiers. The Scn2a(Q54) transgenic mouse model has a sodium channel mutation and exhibits epilepsy with strain-dependent severity. We previously mapped modifier loci that influence Scn2a(Q54) phenotype severity and identified Kcnv2, encoding the voltage-gated potassium channel subunit Kv8.2, as a candidate modifier. In this study, we demonstrate a threefold increase in hippocampal Kcnv2 expression associated with more severe epilepsy. In vivo exacerbation of the phenotype by Kcnv2 transgenes supports its identification as an epilepsy modifier. The contribution of KCNV2 to human epilepsy susceptibility is supported by identification of two nonsynonymous variants in epilepsy patients that alter function of Kv2.1/Kv8.2 heterotetrameric potassium channels. Our results demonstrate that altered potassium subunit function influences epilepsy susceptibility and implicate Kcnv2 as an epilepsy gene.
电压门控离子通道的突变是几种类型癫痫的原因。具有相同突变的个体中，遗传癫痫通常表现出不同的严重程度，这可能是由于遗传修饰因子的变异所致。Scn2a(Q54)转基因小鼠模型具有钠离子通道突变，并表现出具有菌株依赖性严重程度的癫痫。我们之前曾对影响 Scn2a(Q54)表型严重程度的修饰基因座进行了定位，并确定编码电压门控钾通道亚基 Kv8.2 的 Kcnv2 为候选修饰因子。在这项研究中，我们发现与更严重的癫痫相关的海马体 Kcnv2 表达增加了三倍。体内 Kcnv2 转基因的表型恶化支持了它作为癫痫修饰因子的鉴定。在癫痫患者中发现了两个改变 Kv2.1/Kv8.2 异四聚体钾通道功能的非同义变异，这支持了 KCNV2 对人类癫痫易感性的贡献。我们的研究结果表明，钾亚基功能的改变会影响癫痫的易感性，并暗示 Kcnv2 是一个癫痫基因。
