Alleviating the Effects of Short QT Syndrome Type 3 by Allele-Specific Suppression of the KCNJ2 Mutant Allele

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 KCNJ2 gene. This gene encodes the pore-forming α-subunit of the ion channel that carries the cardiac inward rectifier potassium current (I_K1). These gain-of-function mutations either increase the amplitude of I_K1 or attenuate its rectification. The aim of the present in silico study is to test to which extent allele-specific suppression of the KCNJ2 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_K1 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 KCNJ2 mutant allele is a promising technique in the treatment of SQT3 that should be evaluated in in vitro and in vivo studies.