A Spectrum of Functional Phenotypes Associated with LQT1 Mutations Identified in Patients with Early-Onset Atrial Fibrillation

Abstract

Mutations in KCNQ1, the gene encoding the voltage-gated K+ channel α-subunit that underlies the slowly activating delayed rectifier K+ current (IKs) in the heart, are linked to Type I Long QT Syndrome (LQT1) and Familial Atrial Fibrillation (FAF). Compared to the background prevalence of 0.1%, early-onset atrial fibrillation (patients < 50 years) was observed in ∼2% of LQT1 patients (Johnson et al., Heart Rhythm, 2008). We expressed several LQT1 mutations (P7S, R231H, and T322A) identified in patients with early-onset AF in HEK293 to better understand their functional phenotype. Cells were transfected with cDNA for the auxiliary K+ channel subunit KCNE1 (E1) and WT-, P7S-, R231H-, or T322A-KCNQ (Q1). Whole-cell Q1E1 currents (IQ1E1) were measured using the patch-clamp technique and holding potential of −80mV. We measured I-V relations from these cells by prepulsing from a holding potential of −80 mV to 70 mV in 10-mV increments for 5 seconds, followed by a test-pulse to −50mV for 5 seconds. The peak IQ1E1 measured during the test-pulse was plotted as function of the pre-pulse and the data were described using the Boltzmann equation to calculate the maximally activated IQ1E1 (IMAX), the midpoint potential (V1/2), and slope factor (k). Each mutation generated different functional phenotypes. Compared to cells expressing WT (n=7), cells expressing P7S (n=10) did not alter IMAX (WT=99±9 pA/pF, P7S=93±17 pA/pF), V1/2 (WT=26±3mV, P7S=24±3mV), or k (WT=16±1mV/e-fold ΔI, P7S=16±1mV/e-fold ΔI ). Cells expressing R231H (n=9) generated constitutively active IQ1E1 (R231H=64.07±27.48 pA/pF) at −80 mV that was similar to previously described FAF-linked mutations, and IMAX was not altered (80.09±15.58 pA/pF). In contrast, cells expressing T322A (n=7) generated no IQ1E1. These data demonstrate there is no characteristic IQ1E1 phenotype for LQT1 mutations identified in patients with early-onset AF.