期刊
BRAIN RESEARCH
卷 1676, 期 -, 页码 38-45出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.brainres.2017.09.012
关键词
Model animal; ENU mutagenesis; Tremor; Rats; SK2 channel
资金
- Japan Society for the Promotion of Science [21300153, 16K21501]
- Grants-in-Aid for Scientific Research [16K21501, 26290033] Funding Source: KAKEN
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. 1289N) 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. (C) 2017 Elsevier B.V. All rights reserved.
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