Targeted activation of human ether-a-go-go-related gene channels rescues electrical instability induced by the R56Q+/- long QT syndrome variant.

ABSTRACT:

Aims

Long QT syndrome type 2 (LQTS2) is associated with inherited variants in the cardiac human ether-à-go-go-related gene (hERG) K+ channel. However, the pathogenicity of hERG channel gene variants is often uncertain. Using CRISPR-Cas9 gene-edited hiPSC-derived cardiomyocytes (hiPSC-CMs), we investigated the pathogenic mechanism underlying the LQTS-associated hERG R56Q variant and its phenotypic rescue by using the Type 1 hERG activator, RPR260243.

Methods and results

The above approaches enable characterization of the unclear causative mechanism of arrhythmia in the R56Q variant (an N-terminal PAS domain mutation that primarily accelerates channel deactivation) and translational investigation of the potential for targeted pharmacologic manipulation of hERG deactivation. Us

SUBMITTER: Venkateshappa R 

PROVIDER: S-EPMC10676460 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature