Ruwald Martin H, Xu Parks Xiaorong, Moss Arthur J, Zareba Wojciech, Baman Jayson, McNitt Scott, Kanters Jorgen K, Shimizu Wataru, Wilde Arthur A, Jons Christian, Lopes Coeli M
Heart Research Follow-up Program, Division of Cardiology, University of Rochester Medical Center, Rochester, New York; Department of Cardiology, Gentofte Hospital, Hellerup, Denmark.
Cardiovascular Research Institute, Department of Medicine, University of Rochester, Rochester, New York.
Heart Rhythm. 2016 Jan;13(1):122-31. doi: 10.1016/j.hrthm.2015.08.033. Epub 2015 Aug 28.
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-codon and frameshift mutations, has been associated with a lower risk of cardiac events in patients with LQT1, nonsense mutations have been presumed functionally equivalent.
The purpose of this study was to evaluate clinical differences between 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), which is used as reference; missense c-loop (n = 192); stop-codon (n = 67); frameshift (n = 39); and others (n = 94). The primary outcome was a composite end point of syncope, aborted cardiac arrest, and long QT syndrome-related death (cardiac events). Outcomes were evaluated using the multivariate Cox proportional hazards regression analysis. Standard patch clamp techniques were used.
Compared to patients with missense non-c-loop mutations, the risk of cardiac events was reduced significantly in patients with stop-codon mutations (hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.34-0.96; P = .035), but not in patients with frameshift mutations (HR 1.01; 95% CI 0.58-1.77; P = .97). Our data suggest that currents of the most common stop-codon mutant channel (Q530X) were larger than those of haploinsufficient channels (wild type: 42 ± 6 pA/pF, n = 20; Q530X+wild type: 79 ± 14 pA/pF, n = 20; P < .05) and voltage dependence of activation was altered.
Stop-codon mutations are associated with a lower risk of cardiac events in patients with LQT1, while frameshift mutations are associated with the same risk as the majority of the missense mutations. Our data indicate functional differences between these previously considered equivalent mutation subtypes.
在1型长QT综合征（LQT1）中，已表明突变的位置和类型会影响临床结局。虽然单倍体不足，包括终止密码子和移码突变，与LQT1患者发生心脏事件的较低风险相关，但无义突变被认为在功能上是等效的。
本研究的目的是评估无义突变患者之间的临床差异。
研究样本包括1090例经基因确认有突变的患者。根据突变类型和位置，患者被分为5组：位于非高危细胞质环（c环）的错义突变（n = 698），用作对照；错义c环突变（n = 192）；终止密码子突变（n = 67）；移码突变（n = 39）；以及其他突变（n = 94）。主要结局是晕厥、心脏骤停未遂和长QT综合征相关死亡（心脏事件）的复合终点。使用多变量Cox比例风险回归分析评估结局。采用标准膜片钳技术。
与非c环错义突变患者相比，终止密码子突变患者发生心脏事件的风险显著降低（风险比[HR] 0.57；95%置信区间[CI] 0.34 - 0.96；P = 0.035），但移码突变患者未降低（HR 1.01；95% CI 0.58 - 1.77；P = 0.97）。我们的数据表明，最常见的终止密码子突变通道（Q530X）的电流大于单倍体不足通道的电流（野生型：42 ± 6 pA/pF，n = 20；Q530X + 野生型：79 ± 14 pA/pF，n = 20；P < 0.05），且激活的电压依赖性发生了改变。
终止密码子突变与LQT1患者发生心脏事件的较低风险相关，而移码突变与大多数错义突变的风险相同。我们的数据表明这些先前被认为等效的突变亚型之间存在功能差异。
