Masonic Medical Research Laboratory, Utica, New York 13501, USA.
Heart Rhythm. 2010 Dec;7(12):1872-82. doi: 10.1016/j.hrthm.2010.08.026. Epub 2010 Oct 14.
L-type calcium channel (LTCC) mutations have been associated with Brugada syndrome (BrS), short QT (SQT) syndrome, and Timothy syndrome (LQT8). Little is known about the extent to which LTCC mutations contribute to the J-wave syndromes associated with sudden cardiac death.
The purpose of this study was to identify mutations in the α1, β2, and α2δ subunits of LTCC (Ca(v)1.2) among 205 probands diagnosed with BrS, idiopathic ventricular fibrillation (IVF), and early repolarization syndrome (ERS). CACNA1C, CACNB2b, and CACNA2D1 genes of 162 probands with BrS and BrS+SQT, 19 with IVF, and 24 with ERS were screened by direct sequencing.
METHODS/RESULTS: Overall, 23 distinct mutations were identified. A total of 12.3%, 5.2%, and 16% of BrS/BrS+SQT, IVF, and ERS probands displayed mutations in α1, β2, and α2δ subunits of LTCC, respectively. When rare polymorphisms were included, the yield increased to 17.9%, 21%, and 29.1% for BrS/BrS+SQT, IVF, and ERS probands, respectively. Functional expression of two CACNA1C mutations associated with BrS and BrS+SQT led to loss of function in calcium channel current. BrS probands displaying a normal QTc had additional variations known to prolong the QT interval.
The study results indicate that mutations in the LTCCs are detected in a high percentage of probands with J-wave syndromes associated with inherited cardiac arrhythmias, suggesting that genetic screening of Ca(v) genes may be a valuable diagnostic tool in identifying individuals at risk. These results are the first to identify CACNA2D1 as a novel BrS susceptibility gene and CACNA1C, CACNB2, and CACNA2D1 as possible novel ERS susceptibility genes.
L 型钙通道（LTCC）突变与 Brugada 综合征（BrS）、短 QT（SQT）综合征和 Timothy 综合征（LQT8）有关。目前对于 LTCC 突变在与心源性猝死相关的 J 波综合征中的致病程度知之甚少。
本研究旨在鉴定 205 例 BrS、特发性室颤（IVF）和早期复极综合征（ERS）患者中 LTCC（Ca(v)1.2）的α1、β2 和α2δ亚基突变。通过直接测序筛查了 162 例 BrS 和 BrS+SQT、19 例 IVF 和 24 例 ERS 患者的 CACNA1C、CACNB2b 和 CACNA2D1 基因。
方法/结果：共发现 23 种不同的突变。BrS/BrS+SQT、IVF 和 ERS 患者中分别有 12.3%、5.2%和 16%的患者出现 LTCC 的α1、β2 和α2δ亚基突变。当包括罕见多态性时，BrS/BrS+SQT、IVF 和 ERS 患者的检出率分别增加到 17.9%、21%和 29.1%。与 BrS 和 BrS+SQT 相关的 2 个 CACNA1C 突变的功能表达导致钙通道电流的功能丧失。显示正常 QTc 的 BrS 患者存在已知可延长 QT 间期的其他变异。
研究结果表明，在与遗传性心律失常相关的 J 波综合征患者中，LTCC 突变的检出率较高，提示 Ca(v)基因的遗传筛查可能是识别高危个体的有价值的诊断工具。这些结果首次确定 CACNA2D1 为新的 BrS 易感性基因，CACNA1C、CACNB2 和 CACNA2D1 为新的 ERS 易感性基因。
