Oncotarget

Research Papers:

A novel KCND3 mutation associated with early-onset lone atrial fibrillation

Yuan Huang, Jiawei Yang, Wanyi Xie, Qince Li, Zhipeng Zeng, Haibo Sui, Zhonggui Shan and Zhengrong Huang _

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Oncotarget. 2017; 8:115503-115512. https://doi.org/10.18632/oncotarget.23303

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Abstract

Yuan Huang1,*, Jiawei Yang2,*, Wanyi Xie3,*, Qince Li4,*, Zhipeng Zeng5, Haibo Sui4, Zhonggui Shan6 and Zhengrong Huang5

1National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering, Ministry of Education, Hubei University of Technology, Wuhan 430068, China

2Department of Cardiology, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Jingzhou 434020, China

3Xiamen Key Laboratory of Chiral Drugs, Medical College, Xiamen University, Xiamen 361003, China

4Biocomputing Research Center, School of Computer Science and Technology, Harbin Institute of Technology, Harbin 150001, China

5Department of Cardiology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China

6Department of Cardiovascular Surgery, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China

*These authors have contributed equally to this work

Correspondence to:

Zhengrong Huang, email: huangzhengrong@xmu.edu.cn

Zhonggui Shan, email: szgdoctor@126.com

Keywords: atrial fibrillation; KCND3; transient outward potassium current; patch clamp

Received: October 26, 2017     Accepted: December 05, 2017     Published: December 14, 2017

ABSTRACT

Atrial fibrillation (AF) is the most common arrhythmia in the clinic. While previous studies have identified AF-associated mutations in several genes, the genetic basis for AF remains unclear. Here, we identified a novel T361S missense mutation in potassium voltage-gated channel, shal-related subfamily, member 3 (KCND3) from a Chinese Han family ancestor with lone AF. The wild-type (WT) or mutant T361S of Kv4.3 protein (encoded by KCND3) were co-expressed with the auxiliary subunit K+ channel-Interacting Protein (KChIP2) in HEK293 cells, and transient outward potassium current (Ito) were recorded using patch-clamp methods, and the surface or total protein levels of Kv4.3 were analyzed by western blot. Ito density, measured at 60 mV, for T361S was significantly higher than that for WT. Both the steady-state activation and inactivation curves showed a remarkable hyperpolarizing shift in T361S. Moreover, recovery from inactivation after a 500-ms depolarizing pulse was significantly delayed for T361S compared with that for WT. Mechanistically, the gain of function of Ito elicited by T361S was associated with the increased expression of cell surface and total cell protein of Kv4.3. The computer stimulation revealed that the T361S mutation shortened the action potential duration through an increased Itoin Human Atrial Model. In conclusion, we identified a novel T361S mutation in KCND3 associated with AF in the Chinese Han family. The T361S mutant result in the changes in channel kinetics as well as the up-regulation of Kv4.3 protein, which may be a critical driver for lone AF as observed in the patient.


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