Dominant-negative mutation p.Arg324Thr in KCNA1 impairs Kv1.1 channel function in episodic ataxia

Mov Disord. 2016 Nov;31(11):1743-1748. doi: 10.1002/mds.26737. Epub 2016 Aug 1.


Background: Episodic ataxia type 1 is a rare autosomal dominant neurological disorder caused by mutations in the KCNA1 gene that encodes the α subunit of voltage-gated potassium channel Kv1.1. The functional consequences of identified mutations on channel function do not fully correlate with the clinical phenotype of patients.

Methods: A clinical and genetic study was performed in a family with 5 patients with episodic ataxia type 1, with concurrent epilepsy in 1 of them. Protein expression, modeling, and electrophysiological analyses were performed to study Kv1.1 function.

Results: Whole-genome linkage and candidate gene analyses revealed the novel heterozygous mutation p.Arg324Thr in the KCNA1 gene. The encoded mutant Kv1.1 channel displays reduced currents and altered activation and inactivation.

Conclusions: Taken together, we provide genetic and functional evidence that mutation p.Arg324Thr in the KCNA1 gene is pathogenic and results in episodic ataxia type 1 through a dominant-negative effect. © 2016 International Parkinson and Movement Disorder Society.

Keywords: KCNA1; Kv1.1; electrophysiology; episodic ataxia; mutation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia / genetics*
  • Ataxia / physiopathology*
  • Epilepsy / genetics
  • Epilepsy / physiopathology
  • Female
  • Humans
  • Kv1.1 Potassium Channel / genetics*
  • Male
  • Myokymia / genetics*
  • Myokymia / physiopathology*
  • Pedigree


  • KCNA1 protein, human
  • Kv1.1 Potassium Channel

Supplementary concepts

  • Episodic Ataxia, Type 1