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 1 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 threefold, 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.