KCNJ2 mutation in short QT syndrome 3 results in atrial fibrillation and ventricular proarrhythmia
KCNJ2 mutation in short QT syndrome 3 results in atrial fibrillation and ventricular proarrhythmia
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DOI：
10.1073/pnas.1218154110
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发表时间：
2013-03-12
影响因子：
11.1
通讯作者：
Priori, Silvia G.
中科院分区：
文献类型：
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作者：
Deo, Makarand;Ruan, Yanfei;Priori, Silvia G.
我们描述了一个突变（E299 V）在KCNJ 2，基因编码的强内向整流钾离子通道蛋白（Kir2.1），在一个11岁的男孩。独特的短QT综合征3型表型与心电图上极短的QT间期（200 ms）和阵发性房颤相关。遗传学筛选鉴定出KCNJ 2高度保守区域中的A896 T置换，导致从头突变E299 V。全细胞膜片钳实验表明，E299 V在高于-55 mV的电位下呈现异常大的外向I-κ 1（与野生型相比P < 0.001），这是由于缺乏内向整流。野生型和突变体通道的共表达，以模仿杂合条件仍然导致了一个大的外向电流。免疫共沉淀和动力学分析表明，E299 V和野生型亚型可能异聚化，它们的相互作用损害功能。E299 V突变蛋白的同源组装实际上导致功能的获得。在三个不同的整合水平（单细胞，2D和3D）下使用纯合和杂合条件进行心室兴奋和传播的计算机模拟准确地再现了先证者的心电图表型，包括合并QRS和T波的极短QT间期，ST段缺失和峰值T波。数值实验预测，除了短QT间期，E299 V突变缺乏内向整流应导致房颤。此外，如使用几何精确的三维心室模型（包括His-Purkinje网络）模拟预测的那样，通过钠电流减少20%而导致心室兴奋性轻微降低应增加对危及生命的室性快速性心律失常的脆弱性。
We describe a mutation (E299V) in KCNJ2, the gene that encodes the strong inward rectifier K+ channel protein (Kir2.1), in an 11-y-old boy. The unique short QT syndrome type-3 phenotype is associated with an extremely abbreviated QT interval (200 ms) on ECG and paroxysmal atrial fibrillation. Genetic screening identified an A896T substitution in a highly conserved region of KCNJ2 that resulted in a de novo mutation E299V. Whole-cell patch-clamp experiments showed that E299V presents an abnormally large outward I-kappa 1 at potentials above -55 mV (P < 0.001 versus wild type) due to a lack of inward rectification. Coexpression of wild-type and mutant channels to mimic the heterozygous condition still resulted in a large outward current. Coimmunoprecipitation and kinetic analysis showed that E299V and wild-type isoforms may heteromerize and that their interaction impairs function. The homomeric assembly of E299V mutant proteins actually results in gain of function. Computer simulations of ventricular excitation and propagation using both the homozygous and heterozygous conditions at three different levels of integration (single cell, 2D, and 3D) accurately reproduced the electrocardiographic phenotype of the proband, including an exceedingly short QT interval with merging of the QRS and the T wave, absence of ST segment, and peaked T waves. Numerical experiments predict that, in addition to the short QT interval, absence of inward rectification in the E299V mutation should result in atrial fibrillation. In addition, as predicted by simulations using a geometrically accurate three-dimensional ventricular model that included the His-Purkinje network, a slight reduction in ventricular excitability via 20% reduction of the sodium current should increase vulnerability to life-threatening ventricular tachyarrhythmia.