A novel KCND3 mutation associated with early-onset lone atrial fibrillation

Abstract

Atrial fibrillation (AF) is the most common arrhythmia in the clinic. While previous studies have identified AF-associated mutations in several genes, the genetic basis for AF remains unclear. Here, we identified a novel T361S missense mutation in potassium voltage-gated channel, shal-related subfamily, member 3 (KCND3) from a Chinese Han family ancestor with lone AF. The wild-type (WT) or mutant T361S of K_v4.3 protein (encoded by KCND3) were co-expressed with the auxiliary subunit K⁺ channel-Interacting Protein (KChIP2) in HEK293 cells, and transient outward potassium current (I_to) were recorded using patch-clamp methods, and the surface or total protein levels of K_v4.3 were analyzed by western blot. I_to density, measured at 60 mV, for T361S was significantly higher than that for WT. Both the steady-state activation and inactivation curves showed a remarkable hyperpolarizing shift in T361S. Moreover, recovery from inactivation after a 500-ms depolarizing pulse was significantly delayed for T361S compared with that for WT. Mechanistically, the gain of function of I_to elicited by T361S was associated with the increased expression of cell surface and total cell protein of K_v4.3. The computer stimulation revealed that the T361S mutation shortened the action potential duration through an increased I_toin Human Atrial Model. In conclusion, we identified a novel T361S mutation in KCND3 associated with AF in the Chinese Han family. The T361S mutant result in the changes in channel kinetics as well as the up-regulation of K_v4.3 protein, which may be a critical driver for lone AF as observed in the patient.