Wilders Ronald
Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Int J Mol Sci. 2024 Dec 12;25(24):13351. doi: 10.3390/ijms252413351.
Short QT syndrome type 3 (SQTS3 or SQT3), which is associated with life-threatening cardiac arrhythmias, is caused by heterozygous gain-of-function mutations in the gene. This gene encodes the pore-forming α-subunit of the ion channel that carries the cardiac inward rectifier potassium current (I). These gain-of-function mutations either increase the amplitude of I or attenuate its rectification. The aim of the present in silico study is to test to which extent allele-specific suppression of the mutant allele can alleviate the effects of SQT3, as recently demonstrated in in vitro studies on specific heterozygous mutations associated with long QT syndrome type 1 and 2 and short QT syndrome type 1. To this end, simulations were carried out with the two most recent comprehensive models of a single human ventricular cardiomyocyte. These simulations showed that suppression of the mutant allele can, at least partially, counteract the effects of the mutation on I and restore the action potential duration for each of the four SQT3 mutations that are known by now. We conclude that allele-specific suppression of the mutant allele is a promising technique in the treatment of SQT3 that should be evaluated in in vitro and in vivo studies.
3型短QT综合征（SQTS3或SQT3）与危及生命的心律失常相关，由该基因的杂合功能获得性突变引起。该基因编码携带心脏内向整流钾电流（I）的离子通道的孔形成α亚基。这些功能获得性突变要么增加I的幅度，要么减弱其整流作用。本计算机模拟研究的目的是测试对突变等位基因的等位基因特异性抑制在多大程度上可以缓解SQT3的影响，正如最近在对与1型和2型长QT综合征以及1型短QT综合征相关的特定杂合突变的体外研究中所证明的那样。为此，使用了最新的两种单个人类心室心肌细胞综合模型进行模拟。这些模拟表明，对突变等位基因的抑制至少可以部分抵消突变对I的影响，并恢复目前已知的四种SQT3突变中每一种的动作电位持续时间。我们得出结论，对突变等位基因的等位基因特异性抑制是一种有前景的治疗SQT3的技术，应在体外和体内研究中进行评估。
