A common genetic variant within SCN10A modulates cardiac SCN5A expression

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

doi:10.1172/JCI73140

A common genetic variant within SCN10A modulates cardiac SCN5A expression

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 BarnettIvan P Moskowitz

Hubrecht Institute

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

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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.

Originele taal-2	Engels
Pagina's (van-tot)	1844-52
Aantal pagina's	9
Tijdschrift	Journal of Clinical Investigation
Volume	124
Nummer van het tijdschrift	4
DOI's	https://doi.org/10.1172/JCI73140
Status	Gepubliceerd - 01 apr. 2014

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JCI73140
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van den Boogaard, M., Smemo, S., Burnicka-Turek, O., Arnolds, D. E., van de Werken, H. J. G., Klous, P., McKean, D., Muehlschlegel, J. D., Moosmann, J., Toka, O., Yang, X. H., Koopmann, T. T., Adriaens, M. E., Bezzina, C. R., de Laat, W., Seidman, C., Seidman, J. G., Christoffels, V. M., Nobrega, M. A., ... Moskowitz, I. P. (2014). A common genetic variant within SCN10A modulates cardiac SCN5A expression. Journal of Clinical Investigation, 124(4), 1844-52. https://doi.org/10.1172/JCI73140

@article{1eb3f8551b264ab28a08c3084a423f4b,

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.",

keywords = "Adult, Animals, Arrhythmias, Cardiac, Enhancer Elements, Genetic, Female, Gene Expression Regulation, Genetic Variation, Heart, Humans, Male, Mice, Mice, Transgenic, Myocardium, NAV1.5 Voltage-Gated Sodium Channel, NAV1.8 Voltage-Gated Sodium Channel, Polymorphism, Single Nucleotide, Pregnancy, Promoter Regions, Genetic, RNA, Messenger",

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

year = "2014",

month = apr,

day = "1",

doi = "10.1172/JCI73140",

language = "English",

volume = "124",

pages = "1844--52",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "The American Society for Clinical Investigation",

number = "4",

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van den Boogaard, M, Smemo, S, Burnicka-Turek, O, Arnolds, DE, van de Werken, HJG, Klous, P, McKean, D, Muehlschlegel, JD, Moosmann, J, Toka, O, Yang, XH, Koopmann, TT, Adriaens, ME, Bezzina, CR, de Laat, W, Seidman, C, Seidman, JG, Christoffels, VM, Nobrega, MA, Barnett, P & Moskowitz, IP 2014, 'A common genetic variant within SCN10A modulates cardiac SCN5A expression', Journal of Clinical Investigation, vol. 124, nr. 4, blz. 1844-52. https://doi.org/10.1172/JCI73140

TY - JOUR

T1 - A common genetic variant within SCN10A modulates cardiac SCN5A expression

AU - van den Boogaard, Malou

AU - Smemo, Scott

AU - Burnicka-Turek, Ozanna

AU - Arnolds, David E

AU - van de Werken, Harmen J G

AU - Klous, Petra

AU - McKean, David

AU - Muehlschlegel, Jochen D

AU - Moosmann, Julia

AU - Toka, Okan

AU - Yang, Xinan H

AU - Koopmann, Tamara T

AU - Adriaens, Michiel E

AU - Bezzina, Connie R

AU - de Laat, Wouter

AU - Seidman, Christine

AU - Seidman, J G

AU - Christoffels, Vincent M

AU - Nobrega, Marcelo A

AU - Barnett, Phil

AU - Moskowitz, Ivan P

PY - 2014/4/1

Y1 - 2014/4/1

N2 - 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.

AB - 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.

KW - Adult

KW - Animals

KW - Arrhythmias, Cardiac

KW - Enhancer Elements, Genetic

KW - Female

KW - Gene Expression Regulation

KW - Genetic Variation

KW - Heart

KW - Humans

KW - Male

KW - Mice

KW - Mice, Transgenic

KW - Myocardium

KW - NAV1.5 Voltage-Gated Sodium Channel

KW - NAV1.8 Voltage-Gated Sodium Channel

KW - Polymorphism, Single Nucleotide

KW - Pregnancy

KW - Promoter Regions, Genetic

KW - RNA, Messenger

U2 - 10.1172/JCI73140

DO - 10.1172/JCI73140

M3 - Article

C2 - 24642470

SN - 0021-9738

VL - 124

SP - 1844

EP - 1852

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 4

ER -

A common genetic variant within SCN10A modulates cardiac SCN5A expression

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