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.
  
  
  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.
authors: Cardiovascular Research Center, and Cardiology Division, Massachusetts General Hospital, Boston, USA. dmilan@partners.org
authors: David J
authors: DJ
authors: Milan
authors: Albert M
authors: AM
authors: Kim
authors: Jeffrey R
authors: JR
authors: Winterfield
authors: Ian L
authors: IL
authors: Jones
authors: Arne
authors: A
authors: Pfeufer
authors: Serena
authors: S
authors: Sanna
authors: Dan E
authors: DE
authors: Arking
authors: Adam H
authors: AH
authors: Amsterdam
authors: Khaled M
authors: KM
authors: Sabeh
authors: John D
authors: JD
authors: Mably
authors: David S
authors: DS
authors: Rosenbaum
authors: Randall T
authors: RT
authors: Peterson
authors: Aravinda
authors: A
authors: Chakravarti
authors: Stefan
authors: S
authors: Kääb
authors: Dan M
authors: DM
authors: Roden
authors: Calum A
authors: CA
authors: MacRae
mesh_terms: D000818:Animals; D016757:Death, Sudden, Cardiac / Q000453:epidemiology; D020869:Gene Expression Profiling; D005809:Genes, Regulator / Q000502:physiology*; D006321:Heart / Q000502:physiology*; D006329:Heart Conduction System / Q000502:physiology*; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics; D008564:Membrane Potentials / Q000502:physiology*; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D010641:Phenotype; D012307:Risk Factors; D015027:Zebrafish