Abstract 420: KCNQ1 and KCNE3 Mutations Associated with Atrial Fibrillation
Susceptibility to atrial fibrillation (AF) may have a genetic etiology as evidenced by the association of familial AF with mutations in KCNQ1 and other genes. We re-sequenced KCNQ1 and the cardiac-expressed KCNE genes in a cohort of 401 cases of AF including 98 with lone AF, and a second cohort of 104 subjects with AF developing post-CABG. One KCNE3 and four KCNQ1 mutations were discovered in four subjects. Here, we report the functional characterization of two novel missense KCNQ1 (V215M, V241I) mutations and a missense KCNE3 (R88H) allele. Wild-type (WT) and mutant KCNQ1 channels were functionally characterized by heterologous expression in cultured mammalian cells (CHO-K1), and whole-cell patch clamp recording. When expressed with KCNE1, V215M and V241I generated currents resembling the slow component of the cardiac delayed rectifier current (IKs). The peak current density for V215M-IKs was similar to WT-IKs, while V241I-IKs had ~25% greater current density compared to WT-IKs. The rate of activation of V241I-IKs was significantly faster than WT-IKs at all positive potentials (time to half-maximal current following depolarization at 40 mV: WT-IKs, 114.9 ±27.0 ms, N = 9; V241-IKs, 884.8 ±19.6, N = 9; P <0.001). The time course of deactivation was significantly faster for both mutants (time constant at −30mV after depolarization to 40 mV: WT-IKs, 1773.2 ± 179.1 ms, N =9; V215M-IKs, 393.6 ±18.3 ms, N =10; P<0.001; V241I-IKs, 782.1 99.2 ms, n=9; P<0.001). KCNE3-R88H alters a highly conserved residue in the C-terminus. When expressed in cells stably expressing KCNQ1 and KCNE1 (IKs cells), both WT and mutant KCNE3 evoked rapidly activating, constitutive outward currents. The instantaneous (IInst) and steady state currents (Iss), measured at 150 ms and 1990 ms after the start of the voltage pulse, respectively, were significantly increased in IKs cells expressing R88H-KCNE3 compared to cells expressing WT-KCNE3 (IInst, pA/pF at 60 mV: WT-KCNE3 + IKs, 11.5 ± 1.3 N =8; KCNE3-R88H ± IKs, 23.3 ± 3.5, N =8, P <0.01; ISS, pA/pF at 60 mV: IKs + WT-KCNE3, 23.4 ±1.9, n=8; IKs + KCNE3-R88H, 32.5 ±.9, N=8, P<0.05). The gain-of-function seen with KCNQ1-V241I and KCNE3-R88H may contribute to shortening the atrial refractory period leading to initiation and/or maintenance of AF.