ZFIN ID: ZDB-PUB-080309-4
Deficient zebrafish ether-à-go-go-related gene channel gating causes short-QT syndrome in zebrafish reggae mutants
Hassel, D., Scholz, E.P., Trano, N., Friedrich, O., Just, S., Meder, B., Weiss, D.L., Zitron, E., Marquart, S., Vogel, B., Karle, C.A., Seemann, G., Fishman, M.C., Katus, H.A., and Rottbauer, W.
Date: 2008
Source: Circulation   117(7): 866-875 (Journal)
Registered Authors: Fishman, Mark C., Hassel, David, Just, Steffen, Marquart, Sabine, Rottbauer, Wolfgang, Trano, Nicole
Keywords: none
MeSH Terms:
  • Action Potentials/genetics
  • Amino Acid Substitution
  • Animals
  • Arrhythmias, Cardiac/drug therapy
  • Arrhythmias, Cardiac/embryology
  • Arrhythmias, Cardiac/genetics*
  • Arrhythmias, Cardiac/physiopathology
  • Atrial Fibrillation/drug therapy
  • Atrial Fibrillation/genetics
  • Atrial Fibrillation/physiopathology
  • Disease Models, Animal*
  • Ether-A-Go-Go Potassium Channels/deficiency
  • Ether-A-Go-Go Potassium Channels/genetics
  • Ether-A-Go-Go Potassium Channels/physiology*
  • Genotype
  • Heart/embryology
  • Ion Channel Gating/genetics
  • Mutation, Missense
  • Myocardial Contraction
  • Oocytes
  • Patch-Clamp Techniques
  • Potassium/metabolism
  • Recombinant Fusion Proteins/physiology
  • Sinoatrial Block/drug therapy
  • Sinoatrial Block/genetics
  • Sinoatrial Block/physiopathology
  • Syndrome
  • Terfenadine/therapeutic use
  • Xenopus laevis
  • Zebrafish/embryology
  • Zebrafish/genetics*
  • Zebrafish/physiology
  • Zebrafish Proteins/deficiency
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/physiology*
PubMed: 18250272 Full text @ Circulation
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.