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(Circulation. 2005;111:961-968.)
© 2005 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Novel Mutation in the Per-Arnt-Sim Domain of KCNH2 Causes a Malignant Form of Long-QT Syndrome

Tom Rossenbacker, MD; Kanigula Mubagwa, MD, PhD; Roselie J. Jongbloed, PhD; Johan Vereecke, PhD; Koen Devriendt, MD, PhD; Marc Gewillig, MD; Edward Carmeliet, MD, PhD; Désiré Collen, MD, PhD; Hein Heidbüchel, MD, PhD; Peter Carmeliet, MD, PhD

From the Centre for Transgene Technology and Gene Therapy, Flanders Interuniversitary Institute for Biotechnology (T.R., D.C., P.C.), Laboratory of Experimental Cardiac Surgery (K.M., E.C.), Laboratory of Physiology (J.V.), and Center for Hereditary Heart Diseases (T.R., K.D., M.G., H.H.), KU Leuven, Leuven, Belgium; and Department of Genetics and Cell Biology, University of Maastricht, Maastricht, the Netherlands (R.J.J.).

Correspondence to P. Carmeliet, MD, PhD, Center for Transgene Technology and Gene Therapy, Flanders Interuniversitary Institute for Biotechnology, KU Leuven, Campus Gasthuisberg, Herestraat 49, B-3000, Leuven, Belgium. E-mail peter.carmeliet{at}med.kuleuven.ac.be

Received July 15, 2004; de novo submission received September 30, 2004; accepted November 3, 2004.

Background— It has been proposed that the highest risk for cardiac events in patients with long-QT syndrome subtype 2 (LQT2) is related to mutations in the pore region of the KCNH2 channel. It has also been suggested that a subpopulation of LQT2 patients may benefit from pharmacological therapy with modified KCNH2 channel–blocking drugs.

Methods and Results— In a large LQT2 family (n=33), we have identified a novel nonpore missense mutation (K28E) in the Per-Arnt-Sim (PAS) domain of the KCNH2 channel associated with a malignant phenotype: One third of the suspected gene carriers experienced a major cardiac event. Wild-type and K28E-KCNH2 channels were transiently transfected in HEK293 cells. For the mutant channel, whole-cell patch-clamp analysis showed a reduced current density, a negative shift of voltage-dependent channel availability, and an increased rate of deactivation. Western blot analysis and confocal imaging revealed a trafficking deficiency for the mutant channel that could be rescued by the K⁺ channel blocker E-4031. In cells containing both wild-type and mutant channels, deactivation kinetics were normal. In these cells, reduced current density was restored with E-4031.

Conclusions— Our data suggest that besides pore mutations, mutations in the PAS domain may also exhibit a malignant outcome. Pharmacological restoration of current density is promising as a mutation-specific therapy for patients carrying this trafficking-defective mutant.

Key Words: long-QT syndrome • genetics • electrophysiology • ion channels

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