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      A Novel Gain-of-Function KCND3 Variant Associated with Brugada Syndrome

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          Brugada syndrome (BrS) is a known cause of sudden cardiac death (SCD) characterized by abnormal electrocardiograms and fatal arrhythmias. The variants in KCND3 encoding the K<sub>V</sub>4.3 potassium-channel (the α-subunit of the I<sub>to</sub>) have seldom been reported in BrS. This study aimed to identify novel KCND3 variants associated with BrS and elucidate BrS pathogenesis. High-depth targeted sequencing was performed and the electrophysiological properties of the variants were detected by whole-cell patch-clamp methods in a cultured-cell expressing system. The transcriptional levels of K<sub>V</sub>4.3 in different genotypes were studied by real-time PCR. Western blot was used to assess channel protein expression. A novel KCND3heterozygous variant, c.1292G>A (Arg431His, R431H), was found in the proband. Whole-cell patch-clamp results revealed a gain-of-function phenotype in the variant, with peak I<sub>to</sub> current density increased and faster recovery from inactivation. The expression of mutant Kv4.3 membrane protein increased and the cytoplasmic protein decreased, demonstrating that the membrane/cytoplasm ratio was significantly different. In conclusion, a novel KCND3 heterozygous variant was associated with BrS. The increased I<sub>to</sub> current explained the critical role of KCND3 in the pathogenesis of BrS. Genetic screening for KCND3 could be useful for understanding the pathogenesis of BrS and providing effective risk stratification in the clinic.

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          Most cited references 28

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          J wave syndromes.

          The J wave, also referred to as an Osborn wave, is a deflection immediately following the QRS complex of the surface ECG. When partially buried in the R wave, the J wave appears as J-point elevation or ST-segment elevation. Several lines of evidence have suggested that arrhythmias associated with an early repolarization pattern in the inferior or mid to lateral precordial leads, Brugada syndrome, or arrhythmias associated with hypothermia and the acute phase of ST-segment elevation myocardial infarction are mechanistically linked to abnormalities in the manifestation of the transient outward current (I(to))-mediated J wave. Although Brugada syndrome and early repolarization syndrome differ with respect to the magnitude and lead location of abnormal J-wave manifestation, they can be considered to represent a continuous spectrum of phenotypic expression that we propose be termed J-wave syndromes. This review summarizes our current state of knowledge concerning J-wave syndromes, bridging basic and clinical aspects. We propose to divide early repolarization syndrome into three subtypes: type 1, which displays an early repolarization pattern predominantly in the lateral precordial leads, is prevalent among healthy male athletes and is rarely seen in ventricular fibrillation survivors; type 2, which displays an early repolarization pattern predominantly in the inferior or inferolateral leads, is associated with a higher level of risk; and type 3, which displays an early repolarization pattern globally in the inferior, lateral, and right precordial leads, is associated with the highest level of risk for development of malignant arrhythmias and is often associated with ventricular fibrillation storms. Copyright 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
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            Transient outward current (I(to)) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome.

            Brugada syndrome (BrS) is a sudden death-predisposing genetic condition characterized electrocardiographically by ST segment elevation in the leads V(1)-V(3). Given the prominent role of the transient outward current (I(to)) in BrS pathogenesis, we hypothesized that rare gain-of-function mutations in KCND3 may serve as a pathogenic substrate for BrS. Comprehensive mutational analysis of KCND3-encoded Kv4.3 (I(to)) was conducted using polymerase chain reaction, denaturing high performance liquid chromatography, and direct sequencing of DNA derived from 86 unrelated BrS1-8 genotype-negative BrS patients. DNA from 780 healthy individuals was examined to assess allelic frequency for nonsynonymous variants. Putative BrS-associated Kv4.3 mutations were engineered and coexpressed with wild-type KChIP2 in HEK293 cells. Wild-type and mutant I(to) ion currents were recorded using whole-cell patch clamp. Two BrS1-8 genotype-negative cases possessed novel Kv4.3 missense mutations. Both Kv4.3-L450F and Kv4.3-G600R were absent in 1,560 reference alleles and involved residues highly conserved across species. Both Kv4.3-L450F and Kv4.3-G600R demonstrated a gain-of-function phenotype, increasing peak I(to) current density by 146.2% (n = 15, P <.05) and 50.4% (n = 15, P <.05), respectively. Simulations using a Luo-Rudy II action potential (AP) model demonstrated the stable loss of the AP dome as a result of the increased I(to) maximal conductance associated with the heterozygous expression of either L450F or G600R. These findings provide the first molecular and functional evidence implicating novel KCND3 gain-of-function mutations in the pathogenesis and phenotypic expression of BrS, with the potential for a lethal arrhythmia being precipitated by a genetically enhanced I(to) current gradient within the right ventricle where KCND3 expression is the highest. Copyright © 2011. Published by Elsevier Inc.
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              Molecular determinants of cardiac transient outward potassium current (I(to)) expression and regulation.

              Rapidly activating and inactivating cardiac transient outward K(+) currents, I(to), are expressed in most mammalian cardiomyocytes, and contribute importantly to the early phase of action potential repolarization and to plateau potentials. The rapidly recovering (I(t)(o,f)) and slowly recovering (I(t)(o,s)) components are differentially expressed in the myocardium, contributing to regional heterogeneities in action potential waveforms. Consistent with the marked differences in biophysical properties, distinct pore-forming (alpha) subunits underlie the two I(t)(o) components: Kv4.3/Kv4.2 subunits encode I(t)(o,f), whereas Kv1.4 encodes I(t)(o,s), channels. It has also become increasingly clear that cardiac I(t)(o) channels function as components of macromolecular protein complexes, comprising (four) Kvalpha subunits and a variety of accessory subunits and regulatory proteins that influence channel expression, biophysical properties and interactions with the actin cytoskeleton, and contribute to the generation of normal cardiac rhythms. Derangements in the expression or the regulation of I(t)(o) channels in inherited or acquired cardiac diseases would be expected to increase the risk of potentially life-threatening cardiac arrhythmias. Indeed, a recently identified Brugada syndrome mutation in KCNE3 (MiRP2) has been suggested to result in increased I(t)(o,f) densities. Continued focus in this area seems certain to provide new and fundamentally important insights into the molecular determinants of functional I(t)(o) channels and into the molecular mechanisms involved in the dynamic regulation of I(t)(o) channel functioning in the normal and diseased myocardium. Copyright 2009 Elsevier Inc. All rights reserved.

                Author and article information

                S. Karger AG
                October 2020
                20 August 2020
                : 145
                : 10
                : 623-632
                aDivision of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
                bHubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Wuhan, China
                cState Key Laboratory of Reproductive Medicine, the Center for Clinical Reproductive Medicine and Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
                Author notes
                *Yan Wang, MD, PhD, Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030 (PR China),, , Dao Wu Wang, MD, PhD, Department of Cardiology, State Key Laboratory of Reproductive Medicine, The Center for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029 (PR China),
                508033 Cardiology 2020;145:623–632
                © 2020 S. Karger AG, Basel

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                Page count
                Figures: 4, Pages: 10
                Electrophysiology and Arrhythmia: Research Article


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