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

Ronald Wilders
Academic Medical Center, University of Amsterdam


Abstract

It was recently demonstrated that the effects of long-QT syndrome type 1 can be alleviated by allele-specific 40–60% inhibition of mutant KCNQ1. This gene encodes the pore-forming Kv7.1 α-subunit of the tetrameric ion channel carrying the slow delayed rectifier potassium current (IKs). We questioned whether the effects of long-QT syndrome type 2 (LQT2) can similarly be alleviated by 60% downregulation of mutant KCNH2, encoding the pore-forming Kv11.1 α-subunit of the tetrameric ion channel carrying the rapid delayed rectifier potassium current (IKr). We investigated the effect of 60% inhibition of mutant KCNH2 through computer simulations with the O’Hara–Rudy human ventricular cardiomyocyte model, updated with the IKr Markov model from Li et al. (2017; PMID: 28202629). The model cell was stimulated at 1 Hz. In a situation where mutant and wild-type Kv11.1 proteins are equally expressed and co-assemble randomly, only 6.25% of the 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 LQT2 mutations, the amount of conductive IKr channels increases almost threefold. The associated increase in IKr results in a reduction of the mutation-induced prolongation of the action potential duration at 90% repolarization (APD90) from 357 ms (+135%) to 236 ms (+89%). If the mutant KCNH2 allele can be inhibited by as much as 80%, the amount of conductive IKr channels will increase 4.6-fold and the prolongation in APD90 will be further reduced to 177 ms (+67%). We conclude that allele-specific inhibition of the KCNH2 mutant allele in case of long-QT syndrome type 2 may alleviate the disease.