Deficient Zebrafish Ether-a-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 (2008) Deficient Zebrafish Ether-a-Go-Go related gene channel gating causes Short-QT Syndrome in Zebrafish Reggae mutants. Circulation (Baltimore), 117 7: 866-875. doi:10.1161/CIRCULATIONAHA.107.752220


Author 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
Rottbauer, W
Title Deficient Zebrafish Ether-a-Go-Go related gene channel gating causes Short-QT Syndrome in Zebrafish Reggae mutants
Formatted title
Deficient Zebrafish Ether-à-Go-Go Related Gene Channel Gating Causes Short-QT Syndrome in Zebrafish Reggae Mutants
Journal name Circulation (Baltimore)   Check publisher's open access policy
ISSN 0009-7322
1524-4539
Publication date 2008-01-01
Year available 2008
Sub-type Article (original research)
DOI 10.1161/CIRCULATIONAHA.107.752220
Open Access Status DOI
Volume 117
Issue 7
Start page 866
End page 875
Total pages 10
Editor Dr Loscalzo, J
Place of publication United States
Publisher Lippincott Williams & Wilkins
Language eng
Subject C1
070499 Fisheries Sciences not elsewhere classified
830102 Aquaculture Fin Fish (excl. Tuna)
Formatted abstract
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.

Keyword arrhythmia
Fibrillation
genetics
Ion Channel
Q-Index Code C1
Q-Index Status Confirmed Code

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2009 Higher Education Research Data Collection
School of Biomedical Sciences Publications
 
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Created: Wed, 08 Apr 2009, 00:15:06 EST by Shirley Rey on behalf of School of Biomedical Sciences