Abstract 1049: A Single Amino Acid Deletion in KCNQ1 Associated with a Potent Dominant Negative Effect as a Cause of 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.
Materials and Methods: LQTS patients were screened for disease-associated mutations in KCNQ1, KCNH2, KCNE1, KCNE2 and SCN5A. A novel mutation was identified in KCNQ1 caused by a 3 base deletion at the position 824 – 826, predicting a deletion of Phe at codon 275 in segment 5 of KCNQ1 (DeltaF275). Wild type (WT) and DeltaF275 KCNQ1 constructs were generated and transiently transfected with KCNE1 in CHO-K1 cells to characterize the properties of IKs using conventional whole-cell patch-clamp techniques.
Results: Cells transfected with WT-KCNQ1 and KCNE1 (1:1.3 of molar ratio) produced slowly activating outward current with the characteristics of IKs. Tail currents measured at −40mV following a 2 sec step to +60mV were 381.3±62.6 pA/pF (n=11). Cells transfected with DeltaF275-KCNQ1 and KCNE1 exhibited essentially no current. (Tail current density: 0.8±2.1 pA/pF, n=11, p=0.00001 vs WT). Co-transfection of WT- and DeltaF275-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.
Conclusion: Our data suggest that a DeltaF275 mutation in KCNQ1 is associated with a potent dominant negative effect leading to a loss of function of IKs and that this defect underlies an LQT1 form of the long QT syndrome.