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

被引：18

作者：

Kuramoto, Takashi ^{[1
]}

Yokoe, Mayuko ^{[1
]}

Kunisawa, Naofumi ^{[2
]}

Ohashi, Kana ^{[3
]}

Miyake, Takahito ^{[3
]}

Higuchi, Yuki ^{[1
]}

Yoshimi, Kazuto ^{[1
,5
]}

Mashimo, Tomoji ^{[1
,5
]}

Tanaka, Miyuu ^{[1
,4
]}

Kuwamura, Mitusru ^{[4
]}

Kaneko, Shuji ^{[3
]}

Shimizu, Saki ^{[2
]}

Serikawa, Tadao ^{[1
,2
]}

Ohno, Yukihiro ^{[2
]}

机构：

[1] Kyoto Univ, Inst Lab Anim, Grad Sch Med, Sakyo Ku, Yoshidakonoe Cho, Kyoto 6068501, Japan

[2] Osaka Univ Pharmaceut Sci, Lab Pharmacol, Takatsuki, Osaka 5691094, Japan

[3] Kyoto Univ, Grad Sch Pharmaceut Sci, Dept Mol Pharmacol, Sakyo Ku, Yoshidashimoadachi Cho, Kyoto 6068501, Japan

[4] Osaka Prefecture Univ, Lab Vet Pathol, Izumisano, Osaka 5988531, Japan

[5] Osaka Univ, Inst Lab Anim, Grad Sch Med, Yamada Oka 2-2, Suita, Osaka 5650871, Japan

来源：

BRAIN RESEARCH | 2017年 / 1676卷

基金：

日本学术振兴会;

关键词：

Model animal; ENU mutagenesis; Tremor; Rats; SK2; channel; CENTRAL-NERVOUS-SYSTEM; ABNORMAL MYELINOGENESIS; MOUSE; MYELINATION; EXPRESSION; DISEASE; MODEL;

D O I：

10.1016/j.brainres.2017.09.012

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：38 / 45

页数：8

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