Kcna1-mutant rats dominantly display myokymia, neuromyotonia and spontaneous epileptic seizures.
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.
Institute of Laboratory animals, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Saeko
S
Ishida
Yu
Y
Sakamoto
Takeshi
T
Nishio
Stéphanie
S
Baulac
Mitsuru
M
Kuwamura
Yukihiro
Y
Ohno
Akiko
A
Takizawa
Shuji
S
Kaneko
Tadao
T
Serikawa
Tomoji
T
Mashimo
D000818:Animals; D000932:Antiemetics / Q000627:therapeutic use; D055592:Biophysical Phenomena / Q000235:genetics; D019921:Biotinylation; D001835:Body Weight / Q000187:drug effects; D002220:Carbamazepine / Q000627:therapeutic use; D002478:Cells, Cultured; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004569:Electroencephalography; D004576:Electromyography; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D005038:Ethylnitrosourea / Q000633:toxicity; D018014:Gene Transfer Techniques; D006801:Humans; D020386:Isaacs Syndrome / Q000139:chemically induced / Q000235:genetics* / Q000401:mortality; D051662:Kv1.1 Potassium Channel / Q000187:drug effects / Q000235:genetics*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008958:Models, Molecular; D016296:Mutagenesis / Q000187:drug effects*; D009153:Mutagens / Q000633:toxicity; D020125:Mutation, Missense / Q000187:drug effects* / Q000235:genetics; D020385:Myokymia / Q000139:chemically induced / Q000235:genetics* / Q000401:mortality; D009865:Oocytes; D018408:Patch-Clamp Techniques; D021381:Protein Transport / Q000235:genetics; D011597:Psychomotor Performance / Q000502:physiology; D051381:Rats; D011916:Rats, Inbred F344; D011922:Rats, Mutant Strains; D017421:Sequence Analysis; D012694:Serine / Q000235:genetics; D016019:Survival Analysis; D013550:Swimming; D013912:Threonine / Q000235:genetics; D013997:Time Factors; D014981:Xenopus
D000932:Antiemetics; D009153:Mutagens; D051662:Kv1.1 Potassium Channel; D013912:Threonine; D002220:Carbamazepine; D012694:Serine; D005038:Ethylnitrosourea