title: A novel mutation in the human voltage-gated potassium channel gene (Kv1.1) associates with episodic ataxia type 1 and sometimes with partial epilepsy.
abstract: Episodic ataxia type 1 (EA1) is a rare autosomal dominant disorder characterized by brief episodes of ataxia associated with continuous interattack myokymia. Point mutations in the human voltage-gated potassium channel (Kv1.1) gene on chromosome 12p13 have recently been shown to associate with EA1. A Scottish family with EA1 harbouring a novel mutation in this gene is reported. Of the five affected individuals over three generations, two had partial epilepsy in addition to EA1. The detailed clinical, electrophysiological and molecular genetic findings are presented. The heterozygous point mutation is located at nucleotide position 677 and results in a radical amino acid substitution at a highly conserved position in the second transmembrane domain of the potassium channel. Functional studies indicated that mutant subunits exhibited a dominant negative effect on potassium channel function and would be predicted to impair neuronal repolarization. Potassium channels determine the excitability of neurons and blocking drugs are proconvulsant. A critical review of previously reported EA1 families shows an over-representation of epilepsy in family members with EA1 compared with unaffected members. These observations indicate that this mutation is pathogenic and suggest that the epilepsy in EA1 may be caused by the dysfunctional potassium channel. It is possible that such dysfunction may be relevant to other epilepsies in man.
authors.affiliation: Department of Neurology and Child Development, Royal Hospital for Sick Children, Glasgow, UK.
authors.forename: S M
authors.initials: SM
authors.lastname: Zuberi
authors.forename: L H
authors.initials: LH
authors.lastname: Eunson
authors.forename: A
authors.initials: A
authors.lastname: Spauschus
authors.forename: R
authors.initials: R
authors.lastname: De Silva
authors.forename: J
authors.initials: J
authors.lastname: Tolmie
authors.forename: N W
authors.initials: NW
authors.lastname: Wood
authors.forename: R C
authors.initials: RC
authors.lastname: McWilliam
authors.forename: J B
authors.initials: JB
authors.lastname: Stephenson
authors.forename: J P
authors.initials: JP
authors.lastname: Stephenson
authors.forename: D M
authors.initials: DM
authors.lastname: Kullmann
authors.forename: M G
authors.initials: MG
authors.lastname: Hanna
mesh_terms: D000328:Adult; D001259:Ataxia / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004569:Electroencephalography; D004576:Electromyography; D004828:Epilepsies, Partial / Q000235:genetics*; D005260:Female; D006801:Humans; D015640:Ion Channel Gating; D051662:Kv1.1 Potassium Channel; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010507:Periodicity; D016133:Polymerase Chain Reaction; D015221:Potassium Channels / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated
chemical_list: C496946:KCNA1 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D051662:Kv1.1 Potassium Channel