title: 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.forename: Malou
authors.initials: M
authors.lastname: van den Boogaard
authors.forename: Scott
authors.initials: S
authors.lastname: Smemo
authors.forename: Ozanna
authors.initials: O
authors.lastname: Burnicka-Turek
authors.forename: David E
authors.initials: DE
authors.lastname: Arnolds
authors.forename: Harmen J G
authors.initials: HJ
authors.lastname: van de Werken
authors.forename: Petra
authors.initials: P
authors.lastname: Klous
authors.forename: David
authors.initials: D
authors.lastname: McKean
authors.forename: Jochen D
authors.initials: JD
authors.lastname: Muehlschlegel
authors.forename: Julia
authors.initials: J
authors.lastname: Moosmann
authors.forename: Okan
authors.initials: O
authors.lastname: Toka
authors.forename: Xinan H
authors.initials: XH
authors.lastname: Yang
authors.forename: Tamara T
authors.initials: TT
authors.lastname: Koopmann
authors.forename: Michiel E
authors.initials: ME
authors.lastname: Adriaens
authors.forename: Connie R
authors.initials: CR
authors.lastname: Bezzina
authors.forename: Wouter
authors.initials: W
authors.lastname: de Laat
authors.forename: Christine
authors.initials: C
authors.lastname: Seidman
authors.forename: J G
authors.initials: JG
authors.lastname: Seidman
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Christoffels
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Nobrega
authors.forename: Phil
authors.initials: P
authors.lastname: Barnett
authors.forename: Ivan P
authors.initials: IP
authors.lastname: Moskowitz
mesh_terms: D000328:Adult; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D004742:Enhancer Elements, Genetic; D005260:Female; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006321:Heart / Q000196:embryology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000502:physiology; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; D062559:NAV1.8 Voltage-Gated Sodium Channel; D012333:RNA, Messenger; C568317:SCN10A protein, human; C568320:SCN5A protein, human; C568318:Scn10a protein, mouse; C568321:Scn5a protein, mouse