流行病学、分子和功能证据表明 A572D-SCN5A 不应被视为独立的 LQT3 易感性突变。
Epidemiologic, molecular, and functional evidence suggest A572D-SCN5A should not be considered an independent LQT3-susceptibility mutation.
机构信息
Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
出版信息
Heart Rhythm. 2010 Jul;7(7):912-9. doi: 10.1016/j.hrthm.2010.04.014. Epub 2010 Apr 24.
BACKGROUND
Considering that approximately 2% of Caucasian controls host rare, nonsynonymous variants in the SCN5A-encoded cardiac sodium channel, caution must be exercised when interpreting SCN5A genetic test results for long QT syndrome (LQTS).
OBJECTIVE
The purpose of this study was to determine if A572D-SCN5A is a pathogenic mutation, a possible functional modifier, or background "genetic noise."
METHODS
The frequency of A572D was compared between 3,741 LQTS referral cases (mostly Caucasian) and 1,437 Caucasian controls. A572D-SCN5A was engineered into SCN5A using the most commonly spliced transcript (Q1077del, hH1c clone) in the setting of either H558 or R558 for heterologous expression/patch clamp studies in HEK293 cells.
RESULTS
A572D-SCN5A was detected in 17 (0.45%) of 3,741 cases compared with 7 (0.49%) of 1,437 controls (P = .82). Among the 17 A572D-positive LQTS referrals, 10 (59%) hosted definite LQTS-causing mutations elsewhere (5 KCNQ1, 3 KCNH2, 2 SCN5A). Functional studies showed no gating kinetic or current density differences compared with wild-type channels in the context of H558 but showed moderate dysfunction when expressed in H558R-SCN5A, with which it is invariably associated.
CONCLUSION
There is sufficient evidence to conclude that A572D-SCN5A is not an independent, LQT3-causative mutation. A572D is present in approximately 0.5% of both cases and controls and has a wild-type phenotype when expressed in HEK293 cells. However, in the context of H558R-SCN5A, persistent late sodium current emerges, indicating that A572D/H558R could be a proarrhythmic factor akin to S1103Y. These findings underscore the scrutiny necessary to distinguish truly pathogenic mutations from functional polymorphisms and otherwise innocuous, rare genetic variants in SCN5A. These results also question how much cellular dysfunction for a mutation is required in vitro to support pathogenicity.
背景
考虑到大约 2%的白种人对照者在编码心脏钠离子通道的 SCN5A 中存在罕见的非同义变异，在解释长 QT 综合征（LQTS）的 SCN5A 基因检测结果时必须谨慎。
目的
本研究旨在确定 A572D-SCN5A 是否为致病变异、可能的功能修饰体或背景“遗传噪声”。
方法
在 3741 例 LQTS 转诊病例（主要为白种人）和 1437 例白种人对照者中比较 A572D 的频率。使用最常见的剪接转录本（Q1077del，hH1c 克隆）将 A572D-SCN5A 工程构建到 SCN5A 中，在异源表达/膜片钳研究中设置 H558 或 R558，用于 HEK293 细胞。
结果
与 1437 例对照者中的 7 例（0.49%）相比，在 3741 例病例中检测到 17 例（0.45%）A572D-SCN5A（P=.82）。在 17 例 A572D 阳性的 LQTS 转诊者中，10 例（59%）在其他地方存在明确的导致 LQTS 的突变（5 例 KCNQ1、3 例 KCNH2、2 例 SCN5A）。功能研究表明，与野生型通道相比，在 H558 中没有门控动力学或电流密度差异，但在 H558R-SCN5A 中表达时表现出中度功能障碍，与 H558R-SCN5A 始终相关。
结论
有充分的证据表明 A572D-SCN5A 不是独立的、导致 LQT3 的突变。A572D 存在于大约 0.5%的病例和对照者中，在 HEK293 细胞中表达时具有野生型表型。然而，在 H558R-SCN5A 中，持续存在晚期钠电流，表明 A572D/H558R 可能是一种致心律失常因素，类似于 S1103Y。这些发现强调了在区分真正的致病性突变与功能多态性以及 SCN5A 中其他无害的罕见遗传变异时，需要进行仔细审查。这些结果还质疑在体外支持致病性所需的突变细胞功能障碍程度。
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