Sudden Death-Associated KCNH2 Variants Have Opposing Effects on hERG1NP Function.

hERG1NP is a non-conducting subdomain of the full-length hERG1 channel that is expressed in the nuclei of developing cardiomyocytes. From the nucleus, hERG1NP modulates gating and expression of the full-length hERG1 channel. hERG1NP variants are linked with sudden death in the young, but the impact of these variants on hERG1NP activity has not been studied. To determine the effect of hERG1NP variants on hERG1NP activity, we measured hERG1NP intracellular localization and modulation of membrane current from the full-length hERG1a channel in HEK293 cells. The wildtype hERG1NP suppressed both hERG1a current (I hERG) and protein. We then screened six hERG1NP variants for changes in either intracellular targeting or modulation of hERG1a current. Two variants, R885C and R1047L, disrupted hERG1NP activity by altering nuclear transport or abolishing both I hERG current suppression and nuclear targeting, respectively. Two additional variants, G1036D and Q1068R, enhanced hERG1NP activity by depolarizing hERG1a's voltage dependence of activation via accelerated channel deactivation and recovery from inactivation. Lastly, two variants had no effect: R1035W and R1069S. This work demonstrates that hERG1NP variants associated with sudden death in the young can trigger both loss-of-function and gain-of-function effects on hERG1NP. Additional work is needed to identify specific pathogenic mechanisms of hERG1NP variants.