Sudden Death-Associated KCNH2 Variants Have Opposing Effects on hERG1_NP Function

hERG1_NP is a non-conducting subdomain of the full-length hERG1 channel that is expressed in the nuclei of developing cardiomyocytes. From the nucleus, hERG1_NP modulates gating and expression of the full-length hERG1 channel. hERG1_NP variants are linked with sudden death in the young, but the impact of these variants on hERG1_NP activity has not been studied. To determine the effect of hERG1_NP variants on hERG1_NP activity, we measured hERG1_NP intracellular localization and modulation of membrane current from the full-length hERG1a channel in HEK293 cells. The wildtype hERG1_NP suppressed both hERG1a current (I _hERG) and protein. We then screened six hERG1_NP variants for changes in either intracellular targeting or modulation of hERG1a current. Two variants, R885C and R1047L, disrupted hERG1_NP activity by altering nuclear transport or abolishing both I _hERG current suppression and nuclear targeting, respectively. Two additional variants, G1036D and Q1068R, enhanced hERG1_NP 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 hERG1_NP variants associated with sudden death in the young can trigger both loss-of-function and gain-of-function effects on hERG1_NP. Additional work is needed to identify specific pathogenic mechanisms of hERG1_NP variants.