Alleviating Effects of Long-QT Syndrome Type 2 by Allele-Specific Inhibition of the KCNH2 Mutant Allele

It has recently been demonstrated that the effects of long-QT syndrome type l can be alleviated by allele-specific 40-60% inhibition of the mutant KCNQ1 gene. We investigated whether the effects of long-QT syndrome type 2 (LQTS2) can similarly be alleviated by downregulation of the mutant KCNH2 allele, using the O'Hara-Rudy human ventricular cardiomyocyte model, updated with the rapid delayed rectifier potassium current (IKr) Markov model from Li et al. (2017; PMID: 28202629). If wild-type and mutant KCNH2 proteins are equally expressed and co-assemble randomly, only 6.25% of the tetrameric IKr channels will completely consist of wild-type subunits. Inhibition of the mutant KCNH2 allele by 60% decreases the overall number of IKr channels by 30%. However, if only IKr channels entirely built of wild-type subunits are conductive, as in severe LQTS2 mutations, the amount of conductive IKr channels increases almost three-fold, reducing the mutation-induced prolongation of the APD90 at 1 Hz stimulation from 357 ms (+135%) to 236 ms (+89%). An even higher effect is obtained if the mutant KCNH2 allele can be inhibited by as much as 80%. We conclude that allele-specific inhibition of the KCNH2 mutant allele in case of LQTS2 reduces the mutation-induced action potential prolongation and thus may alleviate the disease.