Stop-codon and C-terminal nonsense mutations are associated with a lower risk of cardiac events in patients with long QT syndrome type 1.
Stop-codon and C-terminal nonsense mutations are associated with a lower risk of cardiac events in patients with long QT syndrome type 1.
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DOI：
10.1016/j.hrthm.2015.08.033
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发表时间：
2016-01
期刊：
影响因子：
5.5
通讯作者：
Lopes CM
中科院分区：
文献类型：
--
作者：
Ruwald MH;Xu Parks X;Moss AJ;Zareba W;Baman J;McNitt S;Kanters JK;Shimizu W;Wilde AA;Jons C;Lopes CM
在长QT综合征1型(LQT1)中，突变的位置和类型已被证明影响临床结果。虽然包括终止密码子和移码突变在内的单倍体功能不全与LQT1患者发生心脏事件的风险较低有关，但无义突变在功能上是相同的。评价无义突变患者的临床差异。研究样本包括1090名基因确认突变的患者。根据突变类型和突变部位将患者分为5组：以高危胞质环(c-loop)为参照的错义非定位(c-loop)(n=698)，c-环(n=192)，终止密码子(ST)(n=67)，移码(FS)(n=39)和其他(n=94)。主要结果是晕厥、流产心脏骤停(ACA)和LQTS相关死亡(心脏事件(CE))的复合终点。采用多因素COX回归分析评价疗效。采用标准膜片钳技术。与错义非c-loop突变相比，ST突变患者发生CE的风险显著降低(HR0.57CI0.34~0.96p=0.035)，而FS突变患者发生CE的风险无显著差异(HR1.01CI0.58~1.77p=0.97)。我们的数据表明，对于最常见的终止密码子突变通道(Q530X)，电流大于单倍体不足通道(pA/pF：wt，42±6，n=20；Q530X+wt，79±14，n=20，P<；0.05)，激活的电压依赖性改变。在LQT1患者中，终止密码子突变与较低的心脏事件风险相关，而移码突变显示出与大多数错义突变相同的风险。我们的数据表明了这些先前认为的等同突变亚型之间的功能差异。
In Long QT Syndrome Type 1 (LQT1), the location and type of mutations have been shown to affect the clinical outcome. Although haploinsufficiency, including stop-codons and frameshift mutations, has been associated with lower risk of cardiac events in LQT1, nonsense mutations have been presumed functionally equivalent. To evaluate clinical differences among patients with nonsense mutations. The study sample comprised 1090 patients with genetically confirmed mutations. Patients were categorized into 5 groups depending on mutation type and location: missense not located in the high risk cytoplasmic-loop (c-loop) (n=698) used as reference, missense c-loop (n=192), stop-codons (ST) (n=67), frameshift (FS) (n=39), and others (n=94). Primary outcome was a composite end point of syncope, aborted cardiac arrest (ACA) and LQTS related death (cardiac events (CE)). Outcomes were evaluated with multivariate Cox regression analysis. Standard patch clamp techniques were used. When compared to missense non c-loop mutations, the risk of CE was reduced significantly in patients with ST mutations (HR 0.57 CI 0.34–0.96 p=0.035), but not in patients with FS mutations (HR 1.01 CI 0.58–1.77 p=0.97). Our data suggest that for the most common stop-codon mutant channel (Q530X), currents were larger than haploinsufficient channels (pA/pF: WT, 42±6, n=20; Q530X+WT, 79±14, n=20, P<0.05) and voltage dependence of activation was altered. Stop-codon mutations are associated with lower risk of cardiac events in LQT1 patients, while frameshift mutations show the same risk as the majority of the missense mutations. Our data indicate functional differences between these previously considered equivalent mutation subtypes.