Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 553-559 |
| Number of pages | 7 |
| Journal | Circulation |
| Volume | 120 |
| Issue number | 7 |
| DOIs | |
| State | Published - Aug 18 2009 |
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Keywords
- Electrophysiology
- Genes
- Ion channels
- Myocardial repolarization
ASJC Scopus subject areas
- Physiology (medical)
- Cardiology and Cardiovascular Medicine
Cite this
Drug-sensitized zebrafish screen identifies multiple genes, including GINS3, as regulators of myocardial repolarization. / Milan, David J.; Kim, Albert M.; Winterfield, Jeffrey R.; Jones, Ian L.; Pfeufer, Arne; Sanna, Serena; Arking, Dan; Amsterdam, Adam H.; Sabeh, Khaled M.; Mably, John D.; Rosenbaum, David S.; Peterson, Randall T.; Chakravarti, Aravinda; Kääb, Stefan; Roden, Dan M.; MacRae, Calum A.
In: Circulation, Vol. 120, No. 7, 18.08.2009, p. 553-559.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Drug-sensitized zebrafish screen identifies multiple genes, including GINS3, as regulators of myocardial repolarization
AU - Milan, David J.
AU - Kim, Albert M.
AU - Winterfield, Jeffrey R.
AU - Jones, Ian L.
AU - Pfeufer, Arne
AU - Sanna, Serena
AU - Arking, Dan
AU - Amsterdam, Adam H.
AU - Sabeh, Khaled M.
AU - Mably, John D.
AU - Rosenbaum, David S.
AU - Peterson, Randall T.
AU - Chakravarti, Aravinda
AU - Kääb, Stefan
AU - Roden, Dan M.
AU - MacRae, Calum A.
PY - 2009/8/18
Y1 - 2009/8/18
N2 - 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.
AB - 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.
KW - Electrophysiology
KW - Genes
KW - Ion channels
KW - Myocardial repolarization
UR - http://www.scopus.com/inward/record.url?scp=69549124105&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=69549124105&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.108.821082
DO - 10.1161/CIRCULATIONAHA.108.821082
M3 - Article
C2 - 19652097
AN - SCOPUS:69549124105
VL - 120
SP - 553
EP - 559
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 7
ER -