Drug-sensitized zebrafish screen identifies multiple genes, including GINS3, as regulators of myocardial repolarization

David J. Milan, Albert M. Kim, Jeffrey R. Winterfield, Ian L. Jones, Arne Pfeufer, Serena Sanna, Dan Arking, Adam H. Amsterdam, Khaled M. Sabeh, John D. Mably, David S. Rosenbaum, Randall T. Peterson, Aravinda Chakravarti, Stefan Kääb, Dan M. Roden, Calum A. MacRae

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)553-559
Number of pages7
JournalCirculation
Volume120
Issue number7
DOIs
StatePublished - Aug 18 2009

Fingerprint

Zebrafish
Pharmaceutical Preparations
Genes
Genome-Wide Association Study
Membrane Potentials
Long QT Syndrome
Gene Regulatory Networks
Sudden Cardiac Death
Human Genome
Sudden Death
Cardiac Myocytes
Cardiac Arrhythmias

Keywords

  • Electrophysiology
  • Genes
  • Ion channels
  • Myocardial repolarization

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Milan, D. J., Kim, A. M., Winterfield, J. R., Jones, I. L., Pfeufer, A., Sanna, S., ... MacRae, C. A. (2009). Drug-sensitized zebrafish screen identifies multiple genes, including GINS3, as regulators of myocardial repolarization. Circulation, 120(7), 553-559. https://doi.org/10.1161/CIRCULATIONAHA.108.821082

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 journalArticle

Milan, DJ, Kim, AM, Winterfield, JR, Jones, IL, Pfeufer, A, Sanna, S, Arking, D, Amsterdam, AH, Sabeh, KM, Mably, JD, Rosenbaum, DS, Peterson, RT, Chakravarti, A, Kääb, S, Roden, DM & MacRae, CA 2009, 'Drug-sensitized zebrafish screen identifies multiple genes, including GINS3, as regulators of myocardial repolarization', Circulation, vol. 120, no. 7, pp. 553-559. https://doi.org/10.1161/CIRCULATIONAHA.108.821082
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. / Drug-sensitized zebrafish screen identifies multiple genes, including GINS3, as regulators of myocardial repolarization. In: Circulation. 2009 ; Vol. 120, No. 7. pp. 553-559.
@article{703456a5dfdb4bcca3b7148a8808df87,
title = "Drug-sensitized zebrafish screen identifies multiple genes, including GINS3, as regulators of myocardial repolarization",
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.",
keywords = "Electrophysiology, Genes, Ion channels, Myocardial repolarization",
author = "Milan, {David J.} and Kim, {Albert M.} and Winterfield, {Jeffrey R.} and Jones, {Ian L.} and Arne Pfeufer and Serena Sanna and Dan Arking and Amsterdam, {Adam H.} and Sabeh, {Khaled M.} and Mably, {John D.} and Rosenbaum, {David S.} and Peterson, {Randall T.} and Aravinda Chakravarti and Stefan K{\"a}{\"a}b and Roden, {Dan M.} and MacRae, {Calum A.}",
year = "2009",
month = "8",
day = "18",
doi = "10.1161/CIRCULATIONAHA.108.821082",
language = "English (US)",
volume = "120",
pages = "553--559",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "7",

}

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 -