High Throughput Screening Identifies a Small Molecule Trafficking Corrector for Long-QT Syndrome Associated KCNQ1 Variants.

ABSTRACT: Congenital long QT syndrome (LQTS) promotes risk for life-threatening cardiac arrhythmia and sudden death in children and young adults. Pathogenic variants in the voltage-gated potassium channel KCNQ1 are the most frequently discovered genetic cause. Most LQTS-associated KCNQ1 variants cause loss-of-function secondary to impaired trafficking of the channel to the plasma membrane. There are currently no therapeutic approaches that address this underlying molecular defect. Using a high throughput screening paradigm, we identified VU0494372, a small molecule that increases total and cell surface expression, and trafficking efficiency of wildtype (WT) KCNQ1 as well as three LQTS-associated variants. Additionally, 16-hour treatment of cells with VU0494372 increased current density for WT KCNQ1

SUBMITTER: Moster KRC 

PROVIDER: S-EPMC12632771 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature