Dual Roles for hERG Channel Subunits: Investigating a KCNH2 Variant in Sudden Infant Death – UROP Symposium

Dual Roles for hERG Channel Subunits: Investigating a KCNH2 Variant in Sudden Infant Death

Aysha Chowdhury

Research Mentor(s): David Jones
Program: Biomed
Authors: Aysha Chowdhury, David K. Jones, PhD

Abstract

KCNH2 encodes hERG (Fig. 1), a voltage-gated potassium channel that plays a critical role in cellular excitability. KCNH2 variants can have severe consequences in both brain and heart, highlighting the need for early diagnosis and appropriate management of patients with KCNH2 variants. Loss-of-function KCNH2 variants cause the cardiac disorder long QT syndrome and increase the risk of sudden cardiac death. In the brain, hERG is associated with neuronal dysfunction, including seizure, epilepsy, and sudden unexpected death in epilepsy, but the mechanisms linking KCNH2 variants with neuronal dysfunction are unknown. A hERG subdomain, hERGNP, regulates gene transcription and ion channel function from the cell nucleus. KCNH2 variants that map to hERGNP are associated with sudden death, suggesting that ​​hERG1NP dysfunction may contribute to the pathogenesis of sudden death associated with KCNH2 variants. To test the impact of SIDS-associated variants on hERGNP activity I generated a hERGNP-encoding construct carrying the SIDS-associated variant, G965A. I will perform experiments/assays to investigate the subcellular localization of the G965A variant and compare it to the wild-type hERG1NP. I predict that G965A will disrupt hERG1NP nuclear targeting. By studying the effects of the G965A mutation on hERGNP activity using confocal microscopy and patch clamp electrophysiology techniques, this research aims to uncover crucial insights into the underlying mechanisms of sudden death associated with KCNH2 variants.

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