Clinical and Functional Genetic Characterization of the Role of Cardiac Calcium Channel Variants in the Early Repolarization Syndrome.
Clinical and Functional Genetic Characterization of the Role of Cardiac Calcium Channel Variants in the Early Repolarization Syndrome.
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DOI：
10.3389/fcvm.2021.680819
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发表时间：
2021
影响因子：
3.6
通讯作者：
Hu D
中科院分区：
文献类型：
--
作者：
Chen X;Barajas-Martínez H;Xia H;Zhang Z;Chen G;Yang B;Jiang H;Antzelevitch C;Hu D
背景：早期复极综合征(ERS)是一种遗传性心脏性猝死(SCD)综合征。本研究旨在探讨心脏钙通道基因的遗传变异在ERS发病机制中的作用及其机制。方法：采用靶基因方法进行基于聚合酶链式反应的下一代测序。对携带钙通道变异的无关ERS先证者进行临床评估，并与匹配的健康对照组进行比较。野生型(WT)和突变型CACNA1C基因与CACNB2b和CACNA2D1在HEK293细胞中共表达，并用全细胞膜片钳技术和共聚焦荧光显微镜进行研究。结果：104例ERS先证者中，16例携带钙通道致病变异基因(年龄32.2±14.6岁，男性87.5%)。诊断时的症状包括晕厥(56.3%)、室性心动过速/纤颤(62.5%)和心源性心脏病(56.3%)。3例(18.8%)有SCD或晕厥家族史。8例患者(50.0%)有单一钙基因罕见变异。另一半携带其他ERS易感基因的罕见变异。与对照组相比，单纯钙突变携带者心率减慢(72.7±8.9vs.65.6±16.1次/分，P<0.0 5)，QT间期缩短(408.2±21.4ms比386.8±16.9ms，P<0.0 1)，Tp-e/Qt延长(0.2 2±0.0 5比0.2 8±0.0 4，P<0.001)。对突变株CACNA1C-P817S(c.2449C>；T)的电生理分析表明，与WT相比，WT的全细胞钙电流密度降低了84.61%(−为3.17±2.53vs.−20.59±3.60pA/pF，n=11和15，P<0.01)。突变通道的杂合性表达与ICA降低51.35%相关。稳态失活向更负的电位移动，也显著加速。共聚焦显微镜显示CACNA1C-P817S的转运受损(WT的外周/中枢强度为0.94±0.10，P817S为0.33±0.12，n=10和9，P<；0.01)。结论：与心脏钙通道编码基因功能丧失(LOF)基因缺陷相关的ERS是一种独特的临床实体，其特征是心率和QTC减慢，以及跨室壁复极离散度增加。在CACNA1C-P817S的情况下，通道到膜的运输受损导致LOF。
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.
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影响因子：
5.5
作者：
Burashnikov, Elena;Pfeiffer, Ryan;Barajas-Martinez, Hector;Delpon, Eva;Hu, Dan;Desai, Mayurika;Borggrefe, Martin;Haeissaguerre, Michel;Kanter, Ronald;Pollevick, Guido D.;Guerchicoff, Alejandra;Laino, Ruben;Marieb, Mark;Nademanee, Koonlawee;Nam, Gi-Byoung;Robles, Roberto;Schimpf, Rainer;Stapleton, Dwight D.;Viskin, Sami;Winters, Stephen;Wolpert, Christian;Zimmern, Samuel;Veltmann, Christian;Antzelevitch, Charles
通讯作者：
Antzelevitch, Charles
DOI：
10.1161/circgenetics.113.000138
发表时间：
2013-06
期刊：
Circulation. Cardiovascular genetics
影响因子：
--
作者：
Boczek NJ;Best JM;Tester DJ;Giudicessi JR;Middha S;Evans JM;Kamp TJ;Ackerman MJ
通讯作者：
Ackerman MJ
影响因子：
24
作者：
Derval, Nicolas;Simpson, Christopher S.;Krahn, Andrew D.
通讯作者：
Krahn, Andrew D.
影响因子：
1.3
作者：
Gussak, I;Antzelevitch, C
通讯作者：
Antzelevitch, C
伴有早期复极和短 QT 综合征的肥厚型心肌病家族中的新型三基因 CACNA1C/DES/MYPN 突变
影响因子：
7.4
作者：
Chen Y;Barajas-Martinez H;Zhu D;Wang X;Chen C;Zhuang R;Shi J;Wu X;Tao Y;Jin W;Wang X;Hu D
通讯作者：
Hu D