Laboratoire de Neurocardiologie, EA4612, Université Lyon 1, Lyon F-69003, France.
Laboratoire de Neurocardiologie, EA4612, Université Lyon 1, Lyon F-69003, France; Unité de Rythmologie, Centre National de Référence des Troubles du Rythme d'Origine Héréditaire, Hôpital Cardiovasculaire et Pneumologique L. Pradel, Hospices Civils de Lyon, Lyon F-69003, France.
Gene. 2014 Feb 25;536(2):348-56. doi: 10.1016/j.gene.2013.11.072. Epub 2013 Dec 12.
A variant of the ether-à-go-go related channel (hERG), p.Arg148Trp (R148W) was found at heterozygous state in two infants who died from sudden infant death syndrome (SIDS), one with documented prolonged QTc and Torsade de Pointes (TdP), and in an adult woman with QTc >500 ms, atrioventricular block and TdP. This variant was previously reported in cases of severe ventricular arrhythmia but very rarely in control subjects. Its classification as mutation or polymorphism awaited electrophysiological characterization.
The properties of this N-terminal, proximal domain, hERG variant were explored in Xenopus oocytes injected with the same amount of RNA encoding for either hERG/WT or hERG/R148W or their equimolar mixture. The human ventricular cell (TNNP) model was used to test the effects of changes in hERG current.
R148W alone produced a current similar to the WT (369 ± 76 nA (mean ± SEM), n=13 versus 342 ± 55 nA in WT, n=13), while the co-expression of 1/2 WT+1/2 R148W lowered the current by 29% versus WT (243 ± 35 nA, n=13, p<0.05). The voltage dependencies of steady-state activation and inactivation were not changed in the variant alone or in co-expression with the WT. The time constants of fast recovery from inactivation and of fast and slow deactivation analyzed between -120 and +20 mV were not changed. The voltage-dependent distribution of the current amplitudes among fast-, slow- and non-deactivating fractions was unaltered. A 6.6% increase in APD90 from 323.5 ms to 345 ms was observed using the human cardiac ventricular myocyte model.
Such a decrease in hERG current as evidenced here when co-expressing the hERG/R148W variant with the WT may have predisposed to the observed long QT syndrome and associated TdP. Therefore, the heterozygous carriers of hERG/R148W may be at risk of cardiac sudden death.
在两名死于婴儿猝死综合征 (SIDS) 的婴儿中，以杂合状态发现了一种醚相关通道 (hERG) 的变体，精氨酸 148 到色氨酸的替换 (R148W)，其中一名婴儿有记录的 QTc 延长和尖端扭转型室性心动过速 (TdP)，另一名成年女性 QTc ＞500ms、房室传导阻滞和 TdP。该变体以前曾在严重室性心律失常病例中报告，但在对照受试者中非常罕见。其作为突变或多态性的分类有待电生理特征分析。
用编码 hERG/WT 或 hERG/R148W 的等量 RNA 注射的非洲爪蟾卵母细胞中探索了该 N 端近端 hERG 变体的特性。使用人类心室细胞 (TNNP) 模型测试 hERG 电流变化的影响。
单独的 R148W 产生的电流类似于 WT（369 ± 76 nA（平均值 ± SEM），n=13 与 WT 的 342 ± 55 nA，n=13），而 1/2 WT+1/2 R148W 的共表达使电流降低 29%，与 WT 相比（243 ± 35 nA，n=13，p<0.05）。单独的变体或与 WT 共表达时，稳态激活和失活的电压依赖性没有改变。在 -120 至 +20 mV 之间分析的快速失活和快速及缓慢去极化的时间常数没有改变。快速、缓慢和非去极化分数之间的电流幅度的电压依赖性分布没有改变。在人类心脏心室肌细胞模型中，观察到 APD90 从 323.5ms 增加到 345ms，增加了 6.6%。
当与 WT 共表达 hERG/R148W 变体时，这里观察到的 hERG 电流减少可能导致观察到的长 QT 综合征和相关的 TdP。因此，hERG/R148W 的杂合携带者可能有发生心脏性猝死的风险。
