Abstract 13864: Functional Characterization of Cardiac Ion Channel Gene Variants in Lone Atrial Fibrillation
Background: Mutations in multiple genes were implicated in lone atrial fibrillation (AF) in which abnormally-functioning mutants may cause ectopic activity or action potential duration shortening. However, few data exist regarding functional characterization of these mutations to identify a causal relationship between a gene variant and occurrence of AF.
Objective: We sought to determine the frequency of potassium and sodium channel gene mutations in patients with lone AF and characterized the electrophysiological properties of the detected mutations.
Methods: We studied 82 patients with lone AF whose onset was 47±11 years old (60 men, mean age 56 years). There were 22 (27%) with familial AF and 51 (62%) with paroxysmal AF. In these patients, we screened for variants in all exons of KCNQ1, KCNH2, KCNE1, KCNE2, KCNJ2 KCNA5, SCN5A, SCN1B, SCN2B, SCN3B, and SCN4B. The potassium and sodium currents were analyzed using whole-cell patch clamp technique.
Results: We identified 2 mutations in KCNH2 (T436M and T895M) and 2 mutations in KCNA5 (H463R and T527M), which were not found in 150 ethnically matched population. We also identified 2 rare variants SCN5A R986Q in one patient and SCN1B T189M in 2 patients. The probands with both KCNH2 mutations had a family history of AF, and those with the other mutations and variants did not. Electrophysiological study showed that the current densities of both KCNH2 mutations were significantly bigger than that of WT. Both slow and fast time constants in T436M KCNH2 channel increased significantly. In contrast, KCNA5 H463R mutant generated no current at all having with dominant negative suppression. KCNA5 T527M was found to be a loss-of-function mutation responsible for AF. Interestingly, SCN5A R986Q mutant reduced sodium current, and SCN1B T189M mutant increased SCN5A-mediated current with a negative shift in the voltage dependence of activation.
Conclusions: In our cohort of lone AF patients, 6 abnormally-functioning variants in cardiac ion channels were identified in 7 probands with a prevalence of approximately 9%. Functional study suggests that these gene variants may predispose patients without underlying heart disease to AF, providing new insights into the molecular etiology involved in the pathogenesis of AF.
- © 2012 by American Heart Association, Inc.