A de novo gain-of-function KCND3 mutation in early repolarization syndrome

Koichiro Takayama; Seiko Ohno; Wei-Guang Ding; Takashi Ashihara; Daisuke Fukumoto; Yuko Wada; Takeru Makiyama; Hiroaki Kise; Minako Hoshiai; Hiroshi Matsuura; Minoru Horie

doi:10.1016/j.hrthm.2019.05.033

A de novo gain-of-function KCND3 mutation in early repolarization syndrome

Heart Rhythm. 2019 Nov;16(11):1698-1706. doi: 10.1016/j.hrthm.2019.05.033. Epub 2019 Jun 4.

Authors

Affiliations

¹ Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan.
² Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan; Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, Japan; Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, Suita, Japan.
³ Department of Physiology, Shiga University of Medical Science, Otsu, Japan.
⁴ Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁵ Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Chuo, Japan.
⁶ Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan. Electronic address: horie@belle.shiga-med.ac.jp.

PMID: 31173922
DOI: 10.1016/j.hrthm.2019.05.033

Abstract

Background: Early repolarization syndrome (ERS) is characterized by J-point elevation on electrocardiograms and ventricular fibrillation (VF). Early repolarization arises from augmentation of the transmural electrical gradient in the cardiac action potential; therefore, the transient outward potassium current (I_to) has been regarded as a key candidate current for elucidating the mechanism of ERS. KCND3 encoding Kv4.3, an α-subunit of the I_to channel, is considered as one of target genes.

Objective: The purpose of this study was to search for novel KCND3 mutations associated with ERS and to clarify the pathogenesis.

Methods: We performed genetic screening for 11 unrelated probands with ERS and analyzed the electrophysiological properties of detected mutations by patch-clamp methods.

Results: A novel de novo KCND3 heterozygous mutation, Gly306Ala (c.917g>c), was found in 1 proband. The proband was a 12-year-old boy, who suffered VF storm and showed significant J-point elevation in multiple leads. Intravenous isoproterenol and subsequent administration of quinidine were effective in preventing VF recurrence and restored the J-point elevation. In electrophysiological analysis, cultured cells expressing mutant Kv4.3 showed significantly increased current densities, slow inactivation, and slow recovery from inactivation compared to wild type. Extracellular application of quinidine significantly restored the inactivation time course in mutant Kv4.3. A simulation study confirmed the relationship between the novel KCND3 mutation and early repolarization on electrocardiograms.

Conclusion: A novel KCND3 heterozygous mutation was found to be associated with ERS. The pathogenesis can be explained by the increased I_to. Genetic screening for KCND3 could be useful for understanding the pathogenesis and selecting effective treatment.

Keywords: Early repolarization syndrome; KCND3; Kv4.3; Quinidine; Transient outward potassium current.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Child
Electrocardiography
Gain of Function Mutation*
Genetic Testing
Humans
Japan
Male
Mutation
Patch-Clamp Techniques
Pedigree
Phenotype
Shal Potassium Channels / genetics*
Ventricular Fibrillation / genetics*

Substances

KCND3 protein, human
Shal Potassium Channels