L51P, a novel mutation in the PAS domain of hERG channel, confers long QT syndrome by impairing channel activation.

The human ether-à-go-go-related gene (hERG) potassium channel mediates the repolarization of ventricular action potentials. Mutations in the KCNH2 cause long QT syndrome (LQTS) and are associated with cardiac arrhythmias and sudden death. Here, we functionally analyzed a mutation of hERG potassium channel (p.L51P), gaining novel insights into clinical genotype-phenotype relationships. Potassium currents were recorded by whole-cell patch clamping in HEK293 cells transiently transfected with wild-type and/or mutant hERG potassium channel. Immunofluorescence assay and confocal imaging were undertaken to study the effects of L51P mutation on channel trafficking. The models of the protein structure of hERG and its mutations are predicted by Amber16 software. Molecular dynamics (MD) of individual protein were performed with Particle Mesh Ewald (PME). The production of MD simulations of hERG-WT and hERG-Mut at constant pressure and temperature were carried out with SHAKE. L51 was a conservative amino acid, located in the Per-Arnt-Sim (PAS) domain of the amino terminus. L51P caused loss of function via impairing channel activation. L51P was predicted to destroy hydrophobic structure in the PAS domain, thus causing the failure of channel opening. In summary, the present study identifies L51P as a novel mutation of hERG potassium channel. L51P mutation mechanistically impairs channel activation, reducing channel functionality. AJTR