Journal Article

Voltage-gated potassium channel KCNV2 (Kv8.2) contributes to epilepsy susceptibility

Kearney, Jennifer A, Jorge, Benjamin S, George, Alfred L. Jr, Campbell, Courtney M, Miller, Alison R, Gurnett, Christina A, Vanoye, Carlos G, Rutter, Elizabeth D

2011

Overview

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 Scn2aQ⁵⁴ transgenic mouse model has a sodium channel mutation and exhibits epilepsy with strain-dependent severity. We previously mapped modifier loci that influence Scn2aQ⁵⁴ 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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Amino Acid Sequence / Animal models / Animals / Biological Sciences / Brain / CHO cells / Complementary DNA / Electric potential / Epilepsy / Epilepsy - genetics / Epilepsy - metabolism / Female / Gene expression / Genetic diversity / Genetic mutation / genetic variation / Genotype & phenotype / Hippocampus / Hippocampus - cytology / Hippocampus - metabolism / Humans / Ion channels / loci / Male / Mice / Mice, Inbred C57BL / Mutation / Neurons / Patch-Clamp Techniques / patients / Phenotype / Phenotypes / Potassium / Potassium channels / Potassium channels (voltage-gated) / Potassium Channels, Voltage-Gated - genetics / Potassium Channels, Voltage-Gated - metabolism / Protein Isoforms - genetics / Protein Isoforms - metabolism / Rodents / Seizures / Sodium channels / Transgenes / Transgenic animals / Transgenic mice