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(Circulation. 2008;117:866-875.)
© 2008 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Deficient Zebrafish Ether-à-Go-Go–Related Gene Channel Gating Causes Short-QT Syndrome in Zebrafish Reggae Mutants

David Hassel, MS^*; Eberhard P. Scholz, MD^*; Nicole Trano, MS^*; Oliver Friedrich, PhD; Steffen Just, PhD; Benjamin Meder, MD; Daniel L. Weiss, PhD; Edgar Zitron, MD; Sabine Marquart, MS; Britta Vogel, MD; Christoph A. Karle, MD; Gunnar Seemann, PhD; Mark C. Fishman, MD; Hugo A. Katus, MD; Wolfgang Rottbauer, MD

From the Department of Internal Medicine III (D.H., E.P.S., N.T., S.J., B.M., E.Z., S.M., B.V., C.A.K., H.A.K., W.R.), University Hospital Heidelberg, Heidelberg, Germany; Department of Physiology and Pathophysiology (O.F.), University of Heidelberg, Heidelberg, Germany; Institute of Biomedical Engineering (D.L.W., G.S.), University of Karlsruhe, Karlsruhe, Germany; and Cardiovascular Research Center (M.C.F.), Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, Mass.

Correspondence to Wolfgang Rottbauer, Department of Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. E-mail wolfgang.rottbauer{at}med.uni-heidelberg.de

Received May 23, 2007; accepted December 7, 2007.

Background— Genetic predisposition is believed to be responsible for most clinically significant arrhythmias; however, suitable genetic animal models to study disease mechanisms and evaluate new treatment strategies are largely lacking.

Methods and Results— In search of suitable arrhythmia models, we isolated the zebrafish mutation reggae (reg), which displays clinical features of the malignant human short-QT syndrome such as accelerated cardiac repolarization accompanied by cardiac fibrillation. By positional cloning, we identified the reg mutation that resides within the voltage sensor of the zebrafish ether-à-go-go–related gene (zERG) potassium channel. The mutation causes premature zERG channel activation and defective inactivation, which results in shortened action potential duration and accelerated cardiac repolarization. Genetic and pharmacological inhibition of zERG rescues recessive reg mutant embryos, which confirms the gain-of-function effect of the reg mutation on zERG channel function in vivo. Accordingly, QT intervals in ECGs from heterozygous and homozygous reg mutant adult zebrafish are considerably shorter than in wild-type zebrafish.

Conclusions— With its molecular and pathophysiological concordance to the human arrhythmia syndrome, zebrafish reg represents the first animal model for human short-QT syndrome.

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Clinical Summaries
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