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Updated: May 6, 2026
Large Scale Zebrafish-Based In vivo Small Molecule Screen
Published on: December 31, 2010
Drug-sensitized zebrafish screen identifies multiple genes, including GINS3, as regulators of myocardial
David J Milan1, Albert M Kim, Jeffrey R Winterfield
1Cardiovascular Research Center, and Cardiology Division, Massachusetts General Hospital, Boston, USA. dmilan@partners.org
Background:
Cardiac repolarization, the process by which cardiomyocytes return to their resting potential after each beat, is a highly regulated process that is critical for heart rhythm stability. Perturbations of cardiac repolarization increase the risk for life-threatening arrhythmias and sudden cardiac death. Although genetic studies of familial long-QT syndromes have uncovered several key genes in cardiac repolarization, the major heritable contribution to this trait remains unexplained. Identification of additional genes may lead to a better understanding of the underlying biology, aid in identification of patients at risk for sudden death, and potentially enable new treatments for susceptible individuals.
Methods And Results:
We extended and refined a zebrafish model of cardiac repolarization by using fluorescent reporters of transmembrane potential. We then conducted a drug-sensitized genetic screen in zebrafish, identifying 15 genes, including GINS3, that affect cardiac repolarization. Testing these genes for human relevance in 2 concurrently completed genome-wide association studies revealed that the human GINS3 ortholog is located in the 16q21 locus, which is strongly associated with QT interval.
Conclusions:
This sensitized zebrafish screen identified 15 novel myocardial repolarization genes. Among these genes is GINS3, the human ortholog of which is a major locus in 2 concurrent human genome-wide association studies of QT interval. These results reveal a novel network of genes that regulate cardiac repolarization.
Insights
Researchers identified 15 novel genes regulating cardiac repolarization using a zebrafish model. The gene GINS3 was found to be significant in human studies of QT interval, revealing a new network of genes involved in heart rhythm.
Area of Science:
- Cardiovascular Biology
- Genetics
- Pharmacology
Background:
- Cardiac repolarization is crucial for heart rhythm stability.
- Dysregulation of repolarization increases arrhythmia and sudden cardiac death risk.
- Previous genetic studies have not fully explained the heritable basis of repolarization traits.
Purpose of the Study:
- To identify novel genes involved in cardiac repolarization.
- To understand the genetic contribution to repolarization abnormalities.
- To potentially discover new therapeutic targets for cardiac arrhythmias.
Main Methods:
- Developed and refined a zebrafish model with fluorescent reporters for transmembrane potential.
- Performed a drug-sensitized genetic screen in zebrafish to identify genes affecting repolarization.
- Validated findings by testing gene relevance in human genome-wide association studies.
Main Results:
- Identified 15 novel genes that influence myocardial repolarization in zebrafish.
- The gene GINS3 was among those identified.
- The human ortholog of GINS3 is located in the 16q21 locus, strongly associated with QT interval in human studies.
Conclusions:
- A sensitized zebrafish screen successfully identified 15 novel genes regulating cardiac repolarization.
- GINS3 is a significant gene identified in this screen, with its human ortholog linked to QT interval.
- These findings uncover a previously unrecognized network of genes critical for cardiac repolarization.
