title: Reconstitution of defective protein trafficking rescues Long-QT syndrome in zebrafish.
abstract: Inherited cardiac arrhythmias are caused by genetic defects in ion channels and associated proteins. Mutations in these channels often do not affect their biophysical properties, but rather interfere with their trafficking to the cell membrane. Accordingly, strategies that could reroute the mutated channels to the membrane should be sufficient to restore the electrical properties of the affected cells, thereby suppressing the underlying arrhythmia. We identified here both, embryonic and adult zebrafish breakdance (bre) as a valuable model for human Long-QT syndrome. Electrocardiograms of adult homozygous bre mutants exhibit significant QT prolongation caused by delayed repolarization of the ventricle. We further show that the bre mutation (zERG(I59S)) disrupts ERG protein trafficking, thereby reducing the amount of active potassium channels on the cell membrane. Interestingly, improvement of channel trafficking by cisapride or dimethylsulfoxid is sufficient to reconstitute ERG channels on the cell membrane in a manner that suffices to suppress the Long-QT induced arrhythmia in breakdance mutant zebrafish. In summary, we show for the first time that therapeutic intervention can cure protein trafficking defects and the associated cardiac arrhythmia in vivo.
authors: Department of Internal Medicine III, University Hospital Heidelberg, Germany.
authors: Benjamin
authors: B
authors: Meder
authors: Eberhard P
authors: EP
authors: Scholz
authors: David
authors: D
authors: Hassel
authors: Christoph
authors: C
authors: Wolff
authors: Steffen
authors: S
authors: Just
authors: Ina M
authors: IM
authors: Berger
authors: Eva
authors: E
authors: Patzel
authors: Christoph
authors: C
authors: Karle
authors: Hugo A
authors: HA
authors: Katus
authors: Wolfgang
authors: W
authors: Rottbauer
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006339:Heart Rate / Q000235:genetics; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009154:Mutation; D021381:Protein Transport / Q000235:genetics; D018754:Ventricular Dysfunction / Q000235:genetics / Q000503:physiopathology; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C527141:Erg protein, zebrafish; D051638:Ether-A-Go-Go Potassium Channels; D029961:Zebrafish Proteins