Deficient zebrafish ether-à-go-go-related gene channel gating causes short-QT syndrome in zebrafish reggae mutants.
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.


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.
Hassel
David
D
Department of Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
Scholz
Eberhard P
EP
Trano
Nicole
N
Friedrich
Oliver
O
Just
Steffen
S
Meder
Benjamin
B
Weiss
Daniel L
DL
Zitron
Edgar
E
Marquart
Sabine
S
Vogel
Britta
B
Karle
Christoph A
CA
Seemann
Gunnar
G
Fishman
Mark C
MC
Katus
Hugo A
HA
Rottbauer
Wolfgang
W
D000200:Action Potentials / Q000235:genetics; D019943:Amino Acid Substitution; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000196:embryology / Q000235:genetics* / Q000503:physiopathology; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D004195:Disease Models, Animal; D051638:Ether-A-Go-Go Potassium Channels / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005838:Genotype; D006321:Heart / Q000196:embryology; D015640:Ion Channel Gating / Q000235:genetics; D020125:Mutation, Missense; D009200:Myocardial Contraction; D009865:Oocytes; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012848:Sinoatrial Block / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D013577:Syndrome; D016593:Terfenadine / Q000627:therapeutic use; D014982:Xenopus laevis; D015027:Zebrafish / Q000196:embryology / Q000235:genetics* / Q000502:physiology; D029961:Zebrafish Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
C527141:Erg protein, zebrafish; D051638:Ether-A-Go-Go Potassium Channels; D011993:Recombinant Fusion Proteins; D029961:Zebrafish Proteins; D016593:Terfenadine; D011188:Potassium