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 Kv4.3 protein (encoded by KCND3) were co-expressed with the auxiliary subunit K+ channel-Interacting Protein (KChIP2) in HEK293 cells, and transient outward potassium current (Ito) were recorded using patch-clamp methods, and the surface or total protein levels of Kv4.3 were analyzed by western blot. Ito 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 Ito elicited by T361S was associated with the increased expression of cell surface and total cell protein of Kv4.3. The computer stimulation revealed that the T361S mutation shortened the action potential duration through an increased Itoin 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 Kv4.3 protein, which may be a critical driver for lone AF as observed in the patient.
Highlights
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia that results in serious cardiovascular outcomes such as stroke, heart failure and death [1]
A heterozygous www.impactjournals.com/oncotarget nucleotide variant of KCND3 (c.1081A>T) leading to the substitution of a threonine residue at position 361 by a serine residue was identified in the proband AF patient and his father. This variant was not detected in the other family members or the 600 Chinese Han control cases (Figure 1A and 1B), and were not found in the database of Human Gene Mutation Data base (HGMD), Ensembl and HapMap
Other atrial fibrillation–associated genes encoding ion channels and their accessory subunits were sequenced in the proband patient
Summary
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia that results in serious cardiovascular outcomes such as stroke, heart failure and death [1]. The prevalence of AF is approximately 1% in the general population and markedly increases in aging populations, occurring in approximately 10%. AF is associated with a five-fold increased risk in the incidence of stroke and other cardiovascular mortalities and is rapidly becoming a public health challenge worldwide [3]. AF is usually associated with recognizable overt cardiovascular disease or precipitating illness, but more than 30% AF cases occurs in the absence of these complications (conventionally referred to as lone AF) [4, 5]. Given that the aforementioned gene mutations occur in low prevalence in AF patients, it is reasonable to hypothesize that additional disease genes remain to be identified
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