J Clin Invest. 2014;124(4):1844–1852. doi:10.1172/JCI73140.
Copyright © 2014, American Society for Clinical Investigation
Research Article
A common genetic variant within SCN10A modulates cardiacSCN5A expression
1Department of Anatomy, Embryology and Physiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
2Department of Human Genetics,
3Department of Pediatrics, and
4Department of Pathology, University of Chicago, Chicago, Illinois, USA.
5Department of Cell Biology, Erasmus Medical Center, Rotterdam, The Netherlands.
6Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands.
7Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
8Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
9Department of Pediatric Cardiology, Children’s Hospital University of Erlangen-Nuremberg, Erlangen, Germany.
10Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Address correspondence to: Vincent M. Christoffels or Phil Barnett, Department of Anatomy, Embryology, and Physiology, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Phone: 3120.5667821; Fax: 3120.6976177; E-mail: v.m.christoffels@amc.uva.nl (V.M. Christoffels). Phone: 3120.5667822; Fax: 3120.6976177; E-mail: p.barnett@amc.uva.nl(P. Barnett). Or to: Marcelo A. Nobrega, Department of Human Genetics, University of Chicago, 920 E. 58th Street CLSC 319, Chicago, Illinois 60637, USA. Phone: 773.834.7919; Fax: 773.834.8470; E-mail: nobrega@uchicago.edu. Or to: Ivan P. Moskowitz, Departments of Pediatrics and Pathology, University of Chicago, 900 E. 57th Street, KCBD, Rm 5118, Chicago, Illinois 60637, USA. Phone: 773.834.0462; Fax: 773.834.2132; E-mail: imoskowitz@uchicago.edu.
Authorship note: Malou van den Boogaard, Scott Smemo, Ozanna Burnicka-Turek, and David E. Arnolds contributed equally to this work. Vincent M. Christoffels, Marcelo A. Nobrega, Phil Barnett, and Ivan P. Moskowitz are co–senior authors.
First published March 18, 2014
Received for publication September 26, 2013, and accepted in revised form January 9, 2014.
Variants in SCN10A, which encodes a voltage-gated sodium channel, are associated with alterations of cardiac conduction parameters and the cardiac rhythm disorder Brugada syndrome; however, it is unclear how SCN10A variants promote dysfunctional cardiac conduction. Here we showed by high-resolution 4C-seq analysis of the Scn10a-Scn5a locus in murine heart tissue that a cardiac enhancer located in Scn10a, encompassing SCN10A functional variant rs6801957, interacts with the promoter of Scn5a, a sodium channel–encoding gene that is critical for cardiac conduction. We observed thatSCN5A transcript levels were several orders of magnitude higher than SCN10A transcript levels in both adult human and mouse heart tissue. Analysis of BAC transgenic mouse strains harboring an engineered deletion of the enhancer within Scn10a revealed that the enhancer was essential forScn5a expression in cardiac tissue. Furthermore, the common SCN10A variant rs6801957 modulatedScn5a expression in the heart. In humans, the SCN10A variant rs6801957, which correlated with slowed conduction, was associated with reduced SCN5A expression. These observations establish a genomic mechanism for how a common genetic variation at SCN10A influences cardiac physiology and predisposes to arrhythmia.