# Sudden death–associated KCNH2 variants exert opposing effects on a nuclear subdomain of the cardiac potassium channel hERG1

## TL;DR

This study shows that genetic variants in a nuclear subdomain of a cardiac potassium channel can cause sudden death in the young by either reducing or increasing the channel's function.

## Contribution

The study reveals that hERG1NP variants can cause both loss-of-function and gain-of-function effects, offering new insights into sudden death mechanisms.

## Key findings

- Two hERG1NP variants (R885C and R1047L) disrupted hERG1NP activity by altering nuclear transport or abolishing current suppression.
- Two variants (G1036D and Q1068R) enhanced hERG1NP activity by altering the voltage dependence of hERG1a channels.
- Two variants (R1035W and R1069S) had no effect on hERG1NP activity.

## Abstract

Human Ether-à-go-go–Related Gene 1 (hERG1) nuclear peptide (hERG1NP) is a recently discovered nonconducting subdomain of the full-length hERG1 channel that is expressed in the nuclei of developing cardiomyocytes. From the nucleus, hERG1NP modulates the gating and expression of the full-length hERG1 channel, introducing an unexplored regulatory mechanism of cell physiology. hERG1NP variants are linked with sudden death in the young, but the impact of these variants on hERG1NP activity is unknown. 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 human embryonic kidney 293 cells. Wildtype hERG1NP suppressed both hERG1a current (IhERG) 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 IhERG 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. Last, 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, but these data demonstrate that hERG1NP variants may represent a novel mechanism of disease.