Abstract 3394: Gain of Function in IKs Secondary to a Mutation in KCNE5 as a Cause of Atrial Fibrillation
Background: Familial forms of atrial fibrillation (AF) have been linked to mutations causing a gain of function in repolarizing currents, including the slowly activating delayed rectifier current, IKs KCNE5 has recently been shown to encode a β subunit that associates with KCNQ1 to modulate the expression of IKs. In the present study, we identify and characterize a novel mutation in KCNE5, leading to a gain of function in IKs, in a patient with AF.
Materials and Methods: 158 Danish patients with AF were screened using a candidate gene approach. A missense mutation, L65F, was identified in KCNE5, which was not observed in 400 ethnically matched alleles. WT-KCNE5 (0.15–1.5 μg) or L65F-KCNE5 (0.3–1.5 μg) was transiently transfected into Chinese Hamster Ovary (CHO) cells stably expressing IKs (KCNQ1+KCNE1) (gift of A. George) and the IKs current was examined using whole cell patch-clamp techniques.
Results: The IKs/CHO cells exhibited slowly activating outward current characteristic of IKs. Transient transfection with 1.5μg of KCNE5 resulted in marked reduction (82%) in IKs tail current. This suppression was concentration-dependent. Cells transfected with L65F-KCNE5 showed significantly larger IKs current compared to cells transfected with WT-KCNE5: 159.1±43.8 vs 17.3±7.3 pA tail current, when transfected with 1.5 μg L65F-KCNE5 (n=16) and WT (n=12), respectively.
Conclusion: Our results provide the first direct line of evidence in support of the hypothesis that a gain of function in IKs secondary to missense mutation in KCNE5 contributes to the development of atrial fibrillation.