Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Proc Natl Acad Sci U S A
2007 Jul 03;10427:11316-21. doi: 10.1073/pnas.0702724104.
Show Gene links
Show Anatomy links
Zebrafish model for human long QT syndrome.
Arnaout R
,
Ferrer T
,
Huisken J
,
Spitzer K
,
Stainier DY
,
Tristani-Firouzi M
,
Chi NC
.
???displayArticle.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.
Babij,
Inhibition of cardiac delayed rectifier K+ current by overexpression of the long-QT syndrome HERG G628S mutation in transgenic mice.
1998, Pubmed
Babij,
Inhibition of cardiac delayed rectifier K+ current by overexpression of the long-QT syndrome HERG G628S mutation in transgenic mice.
1998,
Pubmed
Beis,
Genetic and cellular analyses of zebrafish atrioventricular cushion and valve development.
2005,
Pubmed
Chen,
Mutations affecting the cardiovascular system and other internal organs in zebrafish.
1996,
Pubmed
FRASER,
GENETICAL ASPECTS OF THE CARDIO-AUDITORY SYNDROME OF JERVELL AND LANGE-NIELSEN (CONGENITAL DEAFNESS AND ELECTROCARDIOGRAPHIC ABNORMALITIES).
1964,
Pubmed
Hoorntje,
Homozygous premature truncation of the HERG protein : the human HERG knockout.
1999,
Pubmed
Huang,
Germ-line transmission of a myocardium-specific GFP transgene reveals critical regulatory elements in the cardiac myosin light chain 2 promoter of zebrafish.
2003,
Pubmed
Huisken,
Optical sectioning deep inside live embryos by selective plane illumination microscopy.
2004,
Pubmed
Kopp,
Cardiac performance in the zebrafish breakdance mutant.
2005,
Pubmed
Langheinrich,
Zebrafish embryos express an orthologue of HERG and are sensitive toward a range of QT-prolonging drugs inducing severe arrhythmia.
2003,
Pubmed
Lee,
Targeted disruption of the Kvlqt1 gene causes deafness and gastric hyperplasia in mice.
2000,
Pubmed
Maltsev,
Cardiomyocytes differentiated in vitro from embryonic stem cells developmentally express cardiac-specific genes and ionic currents.
1994,
Pubmed
Milan,
Notch1b and neuregulin are required for specification of central cardiac conduction tissue.
2006,
Pubmed
Milan,
In vivo recording of adult zebrafish electrocardiogram and assessment of drug-induced QT prolongation.
2006,
Pubmed
Nakai,
A high signal-to-noise Ca(2+) probe composed of a single green fluorescent protein.
2001,
Pubmed
Nerbonne,
Studying cardiac arrhythmias in the mouse--a reasonable model for probing mechanisms?
2004,
Pubmed
Roy,
HERG, a primary human ventricular target of the nonsedating antihistamine terfenadine.
1996,
Pubmed
,
Xenbase
Salama,
Mouse models of long QT syndrome.
2007,
Pubmed
Salata,
Cardiac electrophysiological actions of the histamine H1-receptor antagonists astemizole and terfenadine compared with chlorpheniramine and pyrilamine.
1995,
Pubmed
Sanguinetti,
Spectrum of HERG K+-channel dysfunction in an inherited cardiac arrhythmia.
1996,
Pubmed
,
Xenbase
Sedmera,
Functional and morphological evidence for a ventricular conduction system in zebrafish and Xenopus hearts.
2003,
Pubmed
,
Xenbase
Sehnert,
Cardiac troponin T is essential in sarcomere assembly and cardiac contractility.
2002,
Pubmed
Splawski,
Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2.
2000,
Pubmed
Stainier,
Mutations affecting the formation and function of the cardiovascular system in the zebrafish embryo.
1996,
Pubmed
Stainier,
Zebrafish genetics and vertebrate heart formation.
2001,
Pubmed
Taggart,
Human ventricular action potential duration during short and long cycles. Rapid modulation by ischemia.
1996,
Pubmed
