Tremor dominant Kyoto (Trdk) rats carry a missense mutation in the gene encoding the SK2 subunit of small-conductance Ca2+-activated K+ channel.

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. 866 T > A, p. I289N) in Kcnn2, which encodes the SK2 subunit of the small-conductance Ca 2+ -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. [ABSTRACT FROM AUTHOR]