This study was supported by a grant from Japan Heart Foundation/Bayer Yakuhin Research Grant Abroad (YA), grant no. HL 47678 from the National Institutes of Health (CA), and the Masons of New York State and Florida.
A Novel Mutation in KCNQ1 Associated with a Potent Dominant Negative Effect as the Basis for the LQT1 Form of the Long QT Syndrome
Article first published online: 26 JUL 2007
Journal of Cardiovascular Electrophysiology
Volume 18, Issue 9, pages 972–977, September 2007
How to Cite
AIZAWA, Y., UEDA, K., SCORNIK, F., CORDEIRO, J. M., WU, Y., DESAI, M., GUERCHICOFF, A., NAGATA, Y., IESAKA, Y., KIMURA, A., HIRAOKA, M. and ANTZELEVITCH, C. (2007), A Novel Mutation in KCNQ1 Associated with a Potent Dominant Negative Effect as the Basis for the LQT1 Form of the Long QT Syndrome. Journal of Cardiovascular Electrophysiology, 18: 972–977. doi: 10.1111/j.1540-8167.2007.00889.x
Manuscript received 12 February 2007; Revised manuscript received 27 March 2007; Accepted for publication 13 April 2007.
- Issue published online: 26 JUL 2007
- Article first published online: 26 JUL 2007
- ion channel;
- inherited syndrome;
- Torsade de Pointes
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.