A novel mutation in the human voltage-gated potassium channel gene (Kv1.1) associates with episodic ataxia type 1 and sometimes with partial epilepsy

SM Zuberi, LH Eunson, A Spauschus, R De Silva… - Brain, 1999 - academic.oup.com
SM Zuberi, LH Eunson, A Spauschus, R De Silva, J Tolmie, NW Wood, RC McWilliam…
Brain, 1999academic.oup.com
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 …
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.
Oxford University Press