A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene
A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene
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DOI：
10.1161/01.res.0000162101.76263.8c
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发表时间：
2005-04-15
影响因子：
20.1
通讯作者：
Jalife, J
中科院分区：
文献类型：
--
作者：
Priori, SG;Pandit, SV;Jalife, J
短QT综合征（SQTS）导致QTc间期缩短，使患者易发生危及生命的心律失常。到目前为止，已经确定了两种形式的疾病：SQT 1，由HERG（I-Kr）通道中的功能替代增益引起，SQT 2，由KvLQT 1（I-Ks）通道中的功能替代增益引起。在这里，我们确定了一个新的变体，“SQT 3”，它具有独特的心电图表型，其特征在于不对称的T波，和缺陷的基因编码的内向整流Kir2.1（I-K1）通道。单个家族的受影响成员在KCNJ 2基因中具有G514 A取代，导致位置172（D172 N）从天冬氨酸变为天冬酰胺。异源表达的人D172 N通道的全细胞膜片钳研究表明，在-75 mV和-45 mV之间的电位下，与野生型相比，前者的外向I-K1更大（P < 0.05），前者的峰值电流相对于后者发生了偏移（WT，-75 mV; D172 N，-65 mV）。共表达WT和突变体通道以模拟先证者的杂合子条件产生了介于WT和D172 N之间的外向电流。在使用人类心室肌细胞模型的计算机模拟中，增加的外向I-K1大大加速了复极的最后阶段，并缩短了动作电位时程。因此，与其他两种SQTS形式（HERG中的N588 K和KvLQT 1中的V307 L）中的已知突变不同，使用D172 N和WT/D172 N突变的模拟完全解释了高和不对称形状T波的ECG表型。尽管由于缺乏患者的同意，我们无法测试心律失常易感性的诱导，但我们的计算机模拟预测，与WT或HERG或KvLQT 1突变相比，D172 N和WT/D172 N突变的稳态恢复曲线更陡，这可能使SQT 3患者发生折返性心律失常的风险更大。
Short QT syndrome (SQTS) leads to an abbreviated QTc interval and predisposes patients to life-threatening arrhythmias. To date, two forms of the disease have been identified: SQT1, caused by a gain of function substitution in the HERG (I-Kr) channel, and SQT2, caused by a gain of function substitution in the KvLQT1 (I-Ks) channel. Here we identify a new variant, "SQT3", which has a unique ECG phenotype characterized by asymmetrical T waves, and a defect in the gene coding for the inwardly rectifying Kir2.1 (I-K1) channel. The affected members of a single family had a G514A substitution in the KCNJ2 gene that resulted in a change from aspartic acid to asparagine at position 172 (D172N). Whole-cell patch-clamp studies of the heterologously expressed human D172N channel demonstrated a larger outward I-K1 than the wild-type (P < 0.05) at potentials between -75 mV and -45 mV, with the peak current being shifted in the former with respect to the latter (WT, -75 mV; D172N, -65 mV). Coexpression of WT and mutant channels to mimic the heterozygous condition of the proband yielded an outward current that was intermediate between WT and D172N. In computer simulations using a human ventricular myocyte model the increased outward I-K1 greatly accelerated the final phase of repolarization, and shortened the action potential duration. Hence, unlike the known mutations in the two other SQTS forms (N588K in HERG and V307L in KvLQT1), simulations using the D172N and WT/D172N mutations fully accounted for the ECG phenotype of tall and asymmetrically shaped T waves. Although we were unable to test for inducibility of arrhythmia susceptibility due to lack of patients' consent, our computer simulations predict a steeper steady-state restitution curve for the D172N and WT/D172N mutation, compared with WT or to HERG or KvLQT1 mutations, which may predispose SQT3 patients to a greater risk of reentrant arrhythmias.