ExperimentalA de novo gain-of-function KCND3 mutation in early repolarization syndrome
Introduction
Early repolarization (ER) seen on electrocardiograms (ECGs) had been considered nonpathologic for ventricular arrhythmias. However, Haissaguerre et al demonstrated that patients with ER experienced a higher recurrence of idiopathic ventricular fibrillation (VF) than those without ER.1 After this pioneering report, several population studies confirmed the clinical relationship between ER and the occurrence of fatal arrhythmias.2, 3 Therefore, early repolarization syndrome (ERS) is characterized by ER and fatal arrhythmias, including idiopathic VF.4
In humans, the transient outward potassium current (Ito) is larger in the subepicardial layer than in the subendocardial one, creating a transmural electrical gradient in the early phase of the action potential (AP).5 It has been hypothesized that ER is caused by augmentation of this transmural electrical gradient. In an experiment using canine ventricular wedge preparations, an Ito agonist, NS5806, amplified the electrical gradient of the AP, resulting in J-point elevation on pseudo-ECGs and fatal arrhythmias; conversely, an Ito inhibitor, 4-aminopyrodine, suppressed J-point elevation and arrhythmogenicity arising from NS5806.6 Therefore, Ito has been regarded as a key candidate current for elucidating the mechanism underlying ERS. The Ito channel comprises α- and β-subunits, and the α-subunit is Kv4.3 encoded by KCND3.7, 8 Hence, KCND3 has been considered as one of the target genes for ERS. However, apart from 1 recent case report,9 there has been no electrophysiological analysis of KCND3 mutations in ERS patients. We aimed to search for novel KCND3 mutations associated with ERS in a cohort of patients and to clarify the pathogenesis of ERS by electrophysiological analysis.
Section snippets
Patients
The study population comprised 11 consecutive, unrelated probands who had suffered unexplained cardiac arrest with ERS. The ERS was diagnosed by the presence of J-point elevation ≥0.1 mV in >2 inferolateral leads on 12-lead ECG.4 The patients were referred to our laboratories from all over Japan for genetic evaluation. This study was conducted in accordance with the principles outlined in the Declaration of Helsinki and approved by our institutional ethics review board (reference number
Genetic analysis and phenotypic characterization
In 1 of the 11 probands (9%), we identified a heterozygous missense mutation in KCND3, Gly306Ala (c.917 g>c) (Figure 1A). Codon 306 is located in segment 4 of Kv4.3 (Figure 1B), and the amino acid glycine is highly conserved among species (Figure 1C). This mutation has not previously been reported to be associated with ERS or other inherited arrhythmias, and it was not reported in the genomic variation databases. PolyPhen-2, SIFT, and CADD all predicted that the mutant protein would be severely
Discussion
We identified a novel and de novo KCND3 heterozygous mutation, Gly306Ala (c.917g>c), in a sporadic case of ERS. The proband showed obvious J-point elevation during bradycardia and suffered VF storm. Quinidine administration was dramatically effective for preventing recurrence of VF. We demonstrated that the mutation induced gain-of-function changes in Kv4.3, an α-subunit of the Ito channel. The significant characteristics of the mutant Kv4.3 were represented by the markedly slow inactivation
Conclusion
A novel heterozygous Gly306Ala mutation in KCND3 was found to be associated with ERS by electrophysiological analysis and simulation study. The pathogenesis of ERS can be explained by the increased Ito. Although KCND3 mutation carriers seem to be rare in ERS, genetic screening for KCND3 could be useful in understanding the pathogenesis of the disease and selecting the effective treatment.
References (32)
- et al.
J-wave syndromes expert consensus conference report: emerging concepts and gaps in knowledge
Heart Rhythm
(2016) - et al.
Early repolarization syndrome caused by de novo duplication of KCND3 detected by next-generation sequencing
HeartRhythm Case Reports
(2017) - et al.
Significance of integrated in silico transmural ventricular wedge preparation models of human non-failing and failing hearts for safety evaluation of drug candidates
J Pharmacol Toxicol Methods
(2017) - et al.
Identification of large families in early repolarization syndrome
J Am Coll Cardiol
(2013) - et al.
A meta-analysis of genome-wide association studies of the electrocardiographic early repolarization pattern
Heart Rhythm
(2012) - et al.
Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death
Heart Rhythm
(2010) - et al.
ABCC9 is a novel Brugada and early repolarization syndrome susceptibility gene
Int J Cardiol
(2014) - et al.
Transient outward current (I(to)) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome
Heart Rhythm
(2011) - et al.
Characteristics of recurrent ventricular fibrillation associated with inferolateral early repolarization role of drug therapy
J Am Coll Cardiol
(2009) - et al.
Hydroquinidine therapy in Brugada syndrome
J Am Coll Cardiol
(2004)
Sudden cardiac arrest associated with early repolarization
N Engl J Med
Long-term outcome associated with early repolarization on electrocardiography
N Engl J Med
Incidence and prognostic value of early repolarization pattern in the 12-lead electrocardiogram
Circulation
Regional differences in current density and rate-dependent properties of the transient outward current in subepicardial and subendocardial myocytes of human left ventricle
Circulation
A transient outward potassium current activator recapitulates the electrocardiographic manifestations of Brugada syndrome
Cardiovasc Res
Role of the Kv4.3 K+ channel in ventricular muscle. A molecular correlate for the transient outward current
Circ Res
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2022, JACC: Clinical ElectrophysiologyCitation Excerpt :Recently, localized epicardial fibrofatty changes have been proposed to contribute to arrhythmogenesis.134 Genetic variants encoding for sodium and potassium channels are reported in association with clinical cases of ERS,135-137 although this link remains tenuous. The ERP ECG was initially described in 1936 by Shipley and Hallaran,138 and for a long period thereafter, was thought to be a benign phenomenon.139,140
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This work was supported by research grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Grant Numbers 15H04818 to Dr Horie and 15K09689 to Dr Ohno); Health Science Research Grants from the Ministry of Health, Labour and Welfare of Japan for Clinical Research on Measures for Intractable Diseases (Grant Number H27-032 to Dr Horie); and Japan Agency for Medical Research and Development (Grant Number JP17ek0109202 to Dr Ohno).