Kcna1-mutant rats dominantly display myokymia, neuromyotonia and spontaneous epileptic seizures.

Abstract

Mutations in the KCNA1 gene, which encodes for the α subunit of the voltage-gated potassium channel Kv1.1, cause episodic ataxia type 1 (EA1). EA1 is a dominant human neurological disorder characterized by variable phenotypes of brief episodes of ataxia, myokymia, neuromyotonia, and associated epilepsy. Animal models for EA1 include Kcna1-deficient mice, which recessively display severe seizures and die prematurely, and V408A-knock-in mice, which dominantly exhibit stress-induced loss of motor coordination. In the present study, we have identified an N-ethyl-N-nitrosourea-mutagenized rat, named autosomal dominant myokymia and seizures (ADMS), with a missense mutation (S309T) in the voltage-sensor domain, S4, of the Kcna1 gene. ADMS rats dominantly exhibited myokymia, neuromyotonia and generalized tonic-clonic seizures. They also showed cold stress-induced tremor, neuromyotonia, and motor incoordination. Expression studies of homomeric and heteromeric Kv1.1 channels in HEK cells and Xenopus oocytes, showed that, although S309T channels are transferred to the cell membrane surface, they remained non-functional in terms of their biophysical properties, suggesting a dominant-negative effect of the S309T mutation on potassium channel function. ADMS rats provide a new model, distinct from previously reported mouse models, for studying the diverse functions of Kv1.1 in vivo, as well as for understanding the pathology of EA1.

• Authors: Saeko Ishida, Yu Sakamoto, Takeshi Nishio, Stéphanie Baulac, Mitsuru Kuwamura, Yukihiro Ohno, Akiko Takizawa, Shuji Kaneko, Tadao Serikawa, Tomoji Mashimo
• Journal: Brain research (Brain Res) Vol. 1435 Pg. 154-66 (Jan 30 2012) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 22206926 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Video-Audio Media)
• Copyright: Copyright © 2011 Elsevier B.V. All rights reserved.

Chemical References

• Antiemetics
• Mutagens
• Kv1.1 Potassium Channel
• Threonine
• Carbamazepine
• Serine
• Ethylnitrosourea

Topics

• Animals
• Antiemetics (therapeutic use)
• Biophysical Phenomena (genetics)
• Biotinylation
• Body Weight (drug effects)
• Carbamazepine (therapeutic use)
• Cells, Cultured
• Chromosome Mapping
• DNA Mutational Analysis
• Disease Models, Animal
• Electric Stimulation
• Electroencephalography
• Electromyography
• Epilepsy (chemically induced, drug therapy, genetics, mortality)
• Ethylnitrosourea (toxicity)
• Gene Transfer Techniques
• Humans
• Isaacs Syndrome (chemically induced, genetics, mortality)
• Kv1.1 Potassium Channel (drug effects, genetics)
• Male
• Membrane Potentials (drug effects, genetics)
• Mice
• Models, Molecular
• Mutagenesis (drug effects)
• Mutagens (toxicity)
• Mutation, Missense (drug effects, genetics)
• Myokymia (chemically induced, genetics, mortality)
• Oocytes
• Patch-Clamp Techniques
• Protein Transport (genetics)
• Psychomotor Performance (physiology)
• Rats
• Rats, Inbred F344
• Rats, Mutant Strains
• Sequence Analysis
• Serine (genetics)
• Survival Analysis
• Swimming
• Threonine (genetics)
• Time Factors
• Xenopus