A common genetic variant within SCN10A modulates cardiac SCN5A expression
Malou van den Boogaard, … , Phil Barnett, Ivan P. Moskowitz
Malou van den Boogaard, … , Phil Barnett, Ivan P. Moskowitz
Published March 18, 2014
Citation Information: J Clin Invest. 2014;124(4):1844-1852. https://doi.org/10.1172/JCI73140.
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Research Article

A common genetic variant within SCN10A modulates cardiac SCN5A expression

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 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 that SCN5A 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 Scn5a 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.

Authors

Malou van den Boogaard, Scott Smemo, Ozanna Burnicka-Turek, David E. Arnolds, Harmen J.G. van de Werken, Petra Klous, David McKean, Jochen D. Muehlschlegel, Julia Moosmann, Okan Toka, Xinan H. Yang, Tamara T. Koopmann, Michiel E. Adriaens, Connie R. Bezzina, Wouter de Laat, Christine Seidman, J.G. Seidman, Vincent M. Christoffels, Marcelo A. Nobrega, Phil Barnett, Ivan P. Moskowitz

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Figure 3

EnhA and EnhB are necessary for Scn5a cardiac expression.

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EnhA and EnhB are necessary for Scn5a cardiac expression. (A) Modified...
(A) Modified murine BAC RP23-198L19 with LacZ inserted into the endogenous Scn5a translational start site. (B–F) Stable BAC transgenic lines, shown in whole-mount and cross-section histology; arrows indicate AV bundle (blue) and distal bundle branches (red). Pie charts show the distribution of LacZ expression in each genotype class. All studies were performed at 12 weeks of age; the number of independent transgenic lines examined is indicated (each analyzed in triplicate). (B) The WT enhancer demonstrated robust CCS and myocardial expression. (C) EnhA deletion eliminated proximal CCS and myocardial expression. (D) EnhB deletion eliminated distal CCS and myocardial expression. (E) Deletion of both enhancers eliminated CCS and myocardial expression entirely. (F) The minor allele at rs6801957 markedly altered Scn5a-LacZ expression, which was either entirely absent or absent from the atrioventricular bundle and confined to the distal ventricular septum in the majority of cases.