Abstract 13033: A Novel KCND3 Gain-of-Function Mutation Associated with Early Onset of Chronic Lone Atrial Fibrillation
Aims: 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 channel forming subunit KV4.3, leading to an increase in the transient outward potassium current (Ito), have previously been associated with the Brugada Syndrome. Here we aim to determine if mutations in KV4.3 or in the assessor subunit Kv Channel Interacting Protein 2 (KChIP2) are associated with early onset lone AF.
Methods and Results: Two hundred and nine unrelated early onset lone AF patients (< 40 years) were recruited. The entire coding sequence of KCND3 and KChIP2 were bidirectional sequenced and one novel non-synonymous mutation p.A545P were found in KCND3. The p.A545P mutation was not present in the control group (n=432 alleles) or in any publicly available databases. The proband was screened for mutations in genes previously associated with AF and none were found. . The proband was a very tall male with onset of chronic AF at the age of 22. His ECG showed a QTc interval of 380 ms. The ECG also exhibited suspect T-waves which could indicate repolarization abnormalities. The echocardiography revealed nothing abnormal (LA size 3.86cm) and there was no family history of sudden cardiac death or AF. To exclude the possibility of an undetected Brugada Syndrome, a Flecanid test was offered to the patient; the patient has just accepted that offer. Electrophysiological analysis of p.A545P expressed in CHO-K1 cells, revealed that p.A545P peak current density was increased and the onset of inactivation was slower compared to WT, resulting in a significant gain-of-function.
Conclusion: Gain-of-function mutations in KV4.3 have previously been described in Brugada Syndrome, however, this is the first report of a KV4.3 gain-of-function mutation in early onset lone AF. This association of KV4.3 gain-of-function and early onset lone AF further supports the hypothesis that increased potassium current enhances the susceptibility of AF.
- © 2012 by American Heart Association, Inc.