Zebrafish model for human long QT syndrome

doi:10.1073/pnas.0702724104

Zebrafish model for human long QT syndrome

^†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;
^§Department of Pediatrics and Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, 95 South 2000 East, Salt Lake City, UT 84112; and
^‡Harvard Medical School, 260 Longwood Avenue, Boston, MA 02115

Edited by David E. Clapham, Harvard Medical School, Boston, MA, and approved May 21, 2007 (received for review March 23, 2007)

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.

Footnotes

^¶To whom correspondence may be addressed. E-mail: didier_stainier{at}biochem.ucsf.edu, mfirouzi{at}cvrti.utah.edu, or chi{at}medicine.ucsf.edu
Author contributions: R.A., T.F., J.H., D.Y.R.S., M.T.-F., and N.C.C. designed research; R.A., T.F., J.H., K.S., M.T.-F., and N.C.C. performed research; R.A., T.F., J.H., D.Y.R.S., M.T.-F., and N.C.C. analyzed data; and R.A., D.Y.R.S., M.T.-F., and N.C.C. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0702724104/DC1.
Abbreviations:

hpf,

hours postfertilization;

LQTS,

long QT syndrome;

LQT2,

LQTS type 2;

AP,

action potential;

IKr,

rapidly activating delayed rectifier K+ current;

IKs,

slow delayed rectifiers K+ current;

SPIM,

selective plane illumination microscopy.