A novel mutation in KCNQ1 associated with a potent dominant negative effect as the basis for the LQT1 form of the long QT syndrome.

Introduction: Long QT Syndrome (LQTS) is an inherited disorder characterized by prolonged QT intervals and life-threatening polymorphic ventricular tachyarrhythmias. LQT1 caused by KCNQ1 mutations is the most common form of LQTS. Methods and Results: Patients diagnosed with LQTS were screened for disease-associated mutations in KCNQ1, KCNH2, KCNE1, KCNE2, KCNJ2, and SCN5A. A novel mutation was identified in KCNQ1 caused by a three-base deletion at the position 824–826, predicting a deletion of phenylalanine at codon 275 in segment 5 of KCNQ1 (ΔF275). Wild-type (WT) and ΔF275-KCNQ1 constructs were generated and transiently transfected together with a KCNE1 construct in CHO-K1 cells to characterize the properties of the slowly activating delayed rectifier current (IKs) using conventional whole-cell patch–clamp techniques. Cells transfected with WT-KCNQ1 and KCNE1 (1:1.3 molar ratio) produced slowly activating outward current with the characteristics of IKs. Tail current density measured at −40 mV following a two-second step to +60 mV was 381.3 ± 62.6 pA/pF (n = 11). Cells transfected with ΔF275-KCNQ1 and KCNE1 exhibited essentially no current. (Tail current density: 0.8 ± 2.1 pA/pF, n = 11, P = 0.00001 vs WT). Cotransfection of WT- and ΔF275- KCNQ1 (50/50), along with KCNE1, produced little to no current (tail current density: 10.3 ± 3.5 pA/pF, n = 11, P = 0.00001 vs WT alone), suggesting a potent dominant negative effect. Immunohistochemistry showed normal membrane trafficking of ΔF275-KCNQ1. Conclusion: Our data suggest that a ΔF275 mutation in KCNQ1 is associated with a very potent dominant negative effect leading to an almost complete loss of function of IKs and that this defect underlies a LQT1 form of LQTS.