RRC ID 49298
Author Kuramoto T, Yokoe M, Kunisawa N, Ohashi K, Miyake T, Higuchi Y, Yoshimi K, Mashimo T, Tanaka M, Kuwamura M, Kaneko S, Shimizu S, Serikawa T, Ohno Y.
Title Tremor dominant Kyoto (Trdk) rats carry a missense mutation in the gene encoding the SK2 subunit of small-conductance Ca2+-activated K+ channel.
Journal Brain Res
Abstract Tremor dominant Kyoto (Trdk) is an autosomal dominant mutation that appeared in F344/NSlc rats mutagenized with N-ethyl-N-nitrosourea (ENU). In this study, we characterized and genetically analyzed F344-Trdk/+ heterozygous rats. The rats exhibited a tremor that was especially evident around weaning but persisted throughout life. The tremors of F344-Trdk/+ rats were attenuated by drugs effective against essential tremor (ET) but not drugs used to treat Parkinson's disease-related tremor, indicating that the pharmacological phenotype of F344-Trdk/+ rats was similar to human ET. Using positional candidate approach, we identified the Trdk mutation as a missense substitution (c. 866T>A, p. I289N) in Kcnn2, which encodes the SK2 subunit of the small-conductance Ca2+-activated K+ channel. In vitro electrophysiological studies revealed that the I289N mutation diminished SK2 channel activity. These findings demonstrate that F344-Trdk/+ rats represent a novel model of ET, and strongly suggest that Kcnn2 is the causative gene for the tremor phenotype in F344-Trdk/+ rats.
Volume 1676
Pages 38-45
Published 2017-12-1
DOI 10.1016/j.brainres.2017.09.012
PII S0006-8993(17)30397-9
PMID 28917524
MeSH Animals Anti-Dyskinesia Agents / pharmacology Brain / metabolism Brain / pathology Chromosome Mapping Disease Models, Animal Essential Tremor / drug therapy Essential Tremor / genetics Essential Tremor / metabolism Essential Tremor / pathology HEK293 Cells Humans Immunohistochemistry In Situ Hybridization Mutation, Missense* Patch-Clamp Techniques Phenotype Rats, Inbred F344* Rats, Mutant Strains* Small-Conductance Calcium-Activated Potassium Channels / genetics* Small-Conductance Calcium-Activated Potassium Channels / metabolism Transfection Tremor / drug therapy Tremor / genetics* Tremor / metabolism Tremor / pathology
IF 2.929
Times Cited 3
Rats F344-Trdk/Kyo (strainID=898)