Epidemiologic, molecular, and functional evidence suggest A572D-SCN5A should not be considered an independent LQT3-susceptibility mutation.
Epidemiologic, molecular, and functional evidence suggest A572D-SCN5A should not be considered an independent LQT3-susceptibility mutation.
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DOI：
10.1016/j.hrthm.2010.04.014
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发表时间：
2010-07
期刊：
影响因子：
5.5
通讯作者：
Ackerman MJ
中科院分区：
文献类型：
--
作者：
Tester DJ;Valdivia C;Harris-Kerr C;Alders M;Salisbury BA;Wilde AA;Makielski JC;Ackerman MJ
考虑到大约2%的白人对照在SCN 5A编码的心脏钠通道中存在罕见的非同义变体，因此在解释长QT综合征（LQTS）的SCN 5A基因检测结果时必须谨慎。本研究的目的是确定A572 D-SCN 5A是否是一种致病性突变，一种可能的功能修饰剂，或背景“遗传噪音”。A572 D的频率在3,741例LQTS转诊病例（主要是白人）和1,437例白人对照之间进行了比较。在HEK 293细胞中异源表达/膜片钳研究的H558或R558环境中，使用最常见的剪接转录物（Q1077 del，hH 1c克隆）将A572 D-SCN 5A工程化到SCN 5A中。3，741例病例中有17例（0.45%）检测到A572 D-SCN 5A，而1，437例对照中有7例（0.49%）检测到A572 D-SCN 5A（P = 0.82）。在17例A572 D阳性LQTS转诊病例中，10例（59%）在其他地方存在明确的LQTS致突变（5例KCNQ 1，3例KCNH 2，2例SCN 5A）。功能研究显示，与野生型通道相比，在H558的情况下没有门控动力学或电流密度差异，但在H558 R-SCN 5A中表达时显示出中度功能障碍，其总是相关的。有足够的证据表明，A572 D-SCN 5A不是一个独立的LQT 3致病突变。A572 D存在于约0.5%的病例和对照中，并且当在HEK 293细胞中表达时具有野生型表型。然而，在H558 R-SCN 5A的背景下，出现持续的晚钠电流，表明A572 D/H558 R可能是类似于S1103 Y的促尿素生成因子。这些发现强调了区分真正的致病突变与SCN 5A中的功能多态性和其他无害的罕见遗传变异所需的审查。这些结果还质疑了在体外需要多少细胞功能障碍才能支持致病性。
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). The purpose of this study was to determine if A572D-SCN5A is a pathogenic mutation, a possible functional modifier, or background “genetic noise.” 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. 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. 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.
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