title: Voltage-gated potassium channel KCNV2 (Kv8.2) contributes to epilepsy susceptibility.
abstract: 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.
authors.affiliation: Department of Pharmacology and Medicine, Vanderbilt University, Nashville, TN 37232-0275, USA.
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Jorge
authors.forename: Courtney M
authors.initials: CM
authors.lastname: Campbell
authors.forename: Alison R
authors.initials: AR
authors.lastname: Miller
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Rutter
authors.forename: Christina A
authors.initials: CA
authors.lastname: Gurnett
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Vanoye
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kearney
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004827:Epilepsy / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D018408:Patch-Clamp Techniques; D010641:Phenotype; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics* / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics* / Q000378:metabolism; D019076:Transgenes
chemical_list: C489610:KCNV2 protein, human; C544295:Kcnv2 protein, mouse; D024642:Potassium Channels, Voltage-Gated; D020033:Protein Isoforms