title: Zebrafish model for human long QT syndrome.
abstract: Long QT syndrome (LQTS) is a disorder of ventricular repolarization that predisposes affected individuals to lethal cardiac arrhythmias. To date, an appropriate animal model of inherited LQTS does not exist. The zebrafish is a powerful vertebrate model used to dissect molecular pathways of cardiovascular development and disease. Because fundamental electrical properties of the zebrafish heart are remarkably similar to those of the human heart, the zebrafish may be an appropriate model for studying human inherited arrhythmias. Here we describe the molecular, cellular, and electrophysiological basis of a zebrafish mutant characterized by ventricular asystole. Genetic mapping and direct sequencing identify the affected gene as kcnh2, which encodes the channel responsible for the rapidly activating delayed rectifier K(+) current (I(Kr)). We show that complete loss of functional I(Kr) in embryonic hearts leads to ventricular cell membrane depolarization, inability to generate action potentials (APs), and disrupted calcium release. A small hyperpolarizing current restores spontaneous APs, implying wild-type function of other ionic currents critical for AP generation. Heterozygous fish manifest overt cellular and electrocardiographic evidence for delayed ventricular repolarization. Our findings provide insight into the pathogenesis of homozygous kcnh2 mutations and expand the use of zebrafish mutants as a model system to study human arrhythmias.
authors.affiliation: Department of Biochemistry and Biophysics, Programs in Developmental Biology, Genetics, and Human Genetics, Cardiovascular Research Institute, University of California, 1550 Fourth Street, San Francisco, CA 94158, USA.
authors.forename: Rima
authors.initials: R
authors.lastname: Arnaout
authors.forename: Tania
authors.initials: T
authors.lastname: Ferrer
authors.forename: Jan
authors.initials: J
authors.lastname: Huisken
authors.forename: Kenneth
authors.initials: K
authors.lastname: Spitzer
authors.forename: Didier Y R
authors.initials: DY
authors.lastname: Stainier
authors.forename: Martin
authors.initials: M
authors.lastname: Tristani-Firouzi
authors.forename: Neil C
authors.initials: NC
authors.lastname: Chi
mesh_terms: D000200:Action Potentials / Q000235:genetics; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels; D006323:Heart Arrest / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D008133:Long QT Syndrome / Q000196:embryology / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D014981:Xenopus; D015027:Zebrafish / Q000196:embryology / Q000235:genetics* / Q000502:physiology
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D024642:Potassium Channels, Voltage-Gated