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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Drug-sensitized zebrafish screen identifies multiple genes, including GINS3, as regulators of myocardial repolarization.
Circulation 120, 553-559 (2009)
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.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
electrophysiology; genes; ion channels; myocardial repolarization; long-qt syndrome; modulates cardiac repolarization; interval duration; common variants; atrioventricular-block; molecular physiology; concentric growth; heart; sodium; risk
ISSN (print) / ISBN
0009-7322
e-ISSN
1524-4539
Zeitschrift
Circulation
Quellenangaben
Band: 120,
Heft: 7,
Seiten: 553-559
Verlag
Lippincott Williams & Wilkins
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Human Genetics (IHG)