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

Q: What does this research mean for the field?

Sudden death–associated KCNH2 variants can exert both loss-of-function and gain-of-function effects on the hERG1 nuclear peptide, altering its nuclear localization and modulation of full-length hERG1a channel currents. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.ESTABLISHES_NEW_DIRECTION.

Francisco G. Sanchez-Conde; Mark S. Goodrich; Olivia M. Stack; Louis N.R. Goldberg; Pamela K. Ruzycki; Abhilasha Jain; David Alan Jones

doi:10.1016/j.jbc.2026.111296

February 17, 2026Journal of Biological ChemistryOpen Access

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

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Why the study?

hERG1 nuclear peptide (hERG1 NP) variants are linked with sudden death in the young, but their impact on hERG1 NP activity is unknown.

Structured PICO

P

Population

Human embryonic kidney 293 (HEK293) cells stably expressing the full-length hERG1a channel.

I

Intervention

Transfection with hERG1 nuclear peptide (hERG1 NP) constructs carrying KCNH2 variants (R885C, R1035W, G1036D, R1047L, Q1068R, or R1069S).

C

Comparator

Transfection with wildtype hERG1 NP or green fluorescent protein (GFP).

O

Outcome

hERG1 NP intracellular localization and modulation of membrane current (IhERG) from the full-length hERG1a channel.surrogate

SIDS- and SUDEP-associated hERG1 nuclear peptide variants exert both loss-of-function and gain-of-function effects on the hERG1 channel, revealing a novel mechanism for sudden death in the young.

Limitations

Additional work is needed to identify specific pathogenic mechanisms of hERG1 NP variants in vivo.

Implication

hERG1 NP variants may exert bidirectional effects on channel activity in sudden death; animal data leaves open human relevance and requires validation.

Abstract

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