Abstract
Background: Early repolarization syndrome (ERS) is an inherited sudden cardiac death (SCD) syndrome. The present study investigates the role of genetic variants in cardiac calcium-channel genes in the pathogenesis of ERS and probes the underlying mechanisms.Methods: Polymerase chain reaction–based next-generation sequencing was carried out using a targeted gene approach. Unrelated ERS probands carrying calcium-channel variants were evaluated clinically and compared with matched healthy controls. Wild-type (WT) and mutant CACNA1C genes were coexpressed with CACNB2b and CACNA2D1 in HEK293 cells and studied using whole-cell patch-clamp techniques and confocal fluorescence microscope.Results: Among 104 ERS probands, 16 carried pathogenic variants in calcium-channel genes (32.2 ± 14.6 years old, 87.5% male). The symptoms at diagnosis included syncope (56.3%), ventricular tachycardia/fibrillation (62.5%), and SCD (56.3%). Three cases (18.8%) had a family history of SCD or syncope. Eight patients (50.0%) had a single calcium gene rare variant. The other half carried rare variants in other ERS-susceptible genes. Compared with controls, the heart rate was slower (72.7 ± 8.9 vs. 65.6 ± 16.1 beats/min, *p < 0.05), QTc interval was shorter (408.2 ± 21.4 vs. 386.8 ± 16.9 ms, **p < 0.01), and Tp-e/QT was longer (0.22 ± 0.05 vs. 0.28 ± 0.04, ***p < 0.001) in single calcium mutation carriers. Electrophysiological analysis of one mutation, CACNA1C-P817S (c.2449C>T), revealed that the density of whole-cell calcium current (ICa) was reduced by ~84.61% compared to WT (−3.17 ± 2.53 vs. −20.59 ± 3.60 pA/pF, n = 11 and 15, respectively, **p < 0.01). Heterozygous expression of mutant channels was associated with a 51.35% reduction of ICa. Steady-state inactivation was shifted to more negative potentials and significantly accelerated as well. Confocal microscopy revealed trafficking impairment of CACNA1C-P817S (peripheral/central intensity: 0.94 ± 0.10 in WT vs. 0.33 ± 0.12 in P817S, n = 10 and 9, respectively, **p < 0.01).Conclusions: ERS associated with loss-of-function (LOF) genetic defects in genes encoding the cardiac calcium channel represents a unique clinical entity characterized by decreased heart rate and QTc, as well as increased transmural dispersion of repolarization. In the case of CACNA1C-P817S, impaired trafficking of the channel to the membrane contributes to the LOF.
Highlights
An early repolarizationpattern (ERP), defined as J-point elevation ≥1 mm in ≥2 contiguous inferior and/or lateral leads of a standard 12-lead electrocardiogram (ECG), was traditionally considered as a normal electrocardiographic variant with a benign outcome for several decades [1,2,3,4]
± 0.12, p < 0.01), suggesting that P817S channels were trapped in the endoplasmic reticulum and/or Golgi complex, remaining very few localizing at the sarcolemma. These findings suggest that the loss of current observed with P817S is partially due to an impairment in trafficking of mature CaV1.2 channels from the endoplasmic reticulum/Golgi complex to the cell membrane
A unique clinical entity in 16 unrelated early repolarization syndrome (ERS) probands associated with genetic defects in cardiac calcium-channel is discovered
Summary
An early repolarizationpattern (ERP), defined as J-point elevation ≥1 mm in ≥2 contiguous inferior and/or lateral leads of a standard 12-lead electrocardiogram (ECG), was traditionally considered as a normal electrocardiographic variant with a benign outcome for several decades [1,2,3,4]. Numerous clinical and experimental observations have since confirmed the association between ERP and fatal arrhythmias [7,8,9], giving rise to the term early repolarization syndrome (ERS). Brugada syndrome (BrS) patients carrying calcium-channel mutations have been reported to have briefer QTc intervals and greater risk for cardiac events and sudden cardiac death (SCD) [18]. A small fraction of calcium mutations associated with ERS have been functionally analyzed to ascertain causality and establish a plausible contribution to pathogenesis. The contribution of cardiac calcium-channel mutations to the etiology of ERS remains unclear. Repolarization syndrome (ERS) is an inherited sudden cardiac death (SCD) syndrome. The present study investigates the role of genetic variants in cardiac calcium-channel genes in the pathogenesis of ERS and probes the underlying mechanisms
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