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- Title
A common genetic variant within SCN10A modulates cardiac SCN5A expression.
- Authors
van den Boogaard, Malou; Smemo, Scott; Burnicka-Turek, Ozanna; Arnolds, David E.; van de Werken, Harmen J. G.; Klous, Petra; McKean, David; Muehlschlegel, Jochen D.; Moosmann, Julia; Okan Toka; Xinan H. Yang; Koopmann, Tamara T.; Adriaens, Michiel E.; Bezzina, Connie R.; de Laat, Wouter; Seidman, Christine; Seidman, J. G.; Christoffels, Vincent M.; Nobrega, Marcelo A.; Barnett, Phil
- Abstract
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 SCN1OA variants promote dysfunctional cardiac conduction. Here we showed by high-resolution 4C-seq analysis of the Scn10a-ScnSa locus in murine heart tissue that a cardiac enhancer located in Scn10a, encompassing SCN10A functional variant rs6801957, interacts with the promoter of ScnSa, a sodium channel-encoding gene that is critical for cardiac conduction. We observed that SCNSA 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 for Scn5a expression in cardiac tissue. Furthermore, the common SCN10A variant rs6801957 modulated ScnSa expression in the heart. In humans, the SCN10A variant rs6801957, which correlated with slowed conduction, was associated with reduced SCNSA expression. These observations establish a genomic mechanism for how a common genetic variation at SCN10A influences cardiac physiology and predisposes to arrhythmia.
- Subjects
HEART conduction system; SODIUM channels regulation; BRUGADA syndrome; GENE expression; HEART physiology; ARRHYTHMIA; DISEASE risk factors
- Publication
Journal of Clinical Investigation, 2014, Vol 124, Issue 4, p1844
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI73140