A novel KCND3 gain-of-function mutation associated with early-onset of persistent lone atrial fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and early-onset lone AF has been linked to mutations in genes encoding ion channels. Mutations in the pore forming subunit K(V)4.3 leading to an increase in the transient outward potassium current (I-to) have previously been associated with the Brugada Syndrome. Here we aim to determine if mutations in K(V)4.3 or in the auxiliary subunit K Channel-Interacting Protein (KChIP) 2 are associated with early-onset lone AF. Two hundred and nine unrelated early-onset lone AF patients (40 years) were recruited. The entire coding sequence of KCND3 and KCNIP2 was bidirectionally sequenced. One novel non-synonymous mutation A545P was found in KCND3 and was neither present in the control group (n 432 alleles) nor in any publicly available database. The proband had onset of persistent AF at the age of 22, and no mutations in genes previously associated with AF were found. Electrophysiological analysis of K(V)4.3-A545P expressed in CHO-K1 cells, revealed that peak-current density was increased and the onset of inactivation was slower compared with WT, resulting in a significant gain-of-function both in the absence and the presence of KChIP2. Gain-of-function mutations in K(V)4.3 have previously been described in Brugada Syndrome, however, this is the first report of a K(V)4.3 gain-of-function mutation in early-onset lone AF. This association of K(V)4.3 gain-of-function and early-onset lone AF further supports the hypothesis that increased potassium current enhances AF susceptibility.