Multilevel analyses of SCN5A mutations in arrhythmogenic right ventricular dysplasia/cardiomyopathy suggest non-canonical mechanisms for disease pathogenesis

Cardiovascular Research

Volumn 113, Issue 1, 2017, Pages 102-111

  Te Riele, Anneline S J M ^a,b,c   Agullo Pascual, Esperanza ^d   James, Cynthia A ^a   Leo Macias, Alejandra ^d   Cerrone, Marina ^d   Zhang, Mingliang ^d   Lin, Xianming ^d   Lin, Bin ^d   Rothenberg, Eli ^e   Sobreira, Nara L ^a   Amat Alarcon, Nuria ^a   Marsman, Roos F ^f   Murray, Brittney ^a   Tichnell, Crystal ^a   Van Der Heijden, Jeroen F ^b   Dooijes, Dennis ^b   Van Veen, Toon A B ^b   Tandri, Harikrishna ^a   Fowler, Steven J ^d   Hauer, Richard N W ^b,c   Tomaselli, Gordon ^a   Van Den Berg, Maarten P ^g   Taylor, Matthew R G ^h   Brun, Francesca ⁱ   Sinagra, Gianfranco ⁱ   Wilde, Arthur A M ^f   Mestroni, Luisa ^h   Bezzina, Connie R ^f   Calkins, Hugh ^a   Van Tintelen, J Peter ^f,g   Bu, Lei ^a,d   Delmar, Mario ^a,d   Judge, Daniel P ^a   more..

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

^c INTERUNIVERSITY CARDIOLOGY INSTITUTE OF THE NETHERLANDS   (Netherlands)

^d NEW YORK UNIVERSITY SCHOOL OF MEDICINE   (United States)

^e NEW YORK UNIVERSITY   (United States)

^f ACADEMIC MEDICAL CENTER   (Netherlands)

^g UNIVERSITY MEDICAL CENTER GRONINGEN   (Netherlands)

^h UNIVERSITY OF COLORADO   (United States)

ⁱ UNIVERSITY OF TRIESTE   (Italy)

Author keywords

Arrhythmogenic right ventricular cardiomyopathy; Cardiomyopathy; Genetics; Ion channel electrophysiology; SCN5A

Indexed keywords

NERVE CELL ADHESION MOLECULE; SODIUM CHANNEL NAV1.5; CADHERIN; CDH2 PROTEIN, HUMAN; LEUKOCYTE ANTIGEN; SCN5A PROTEIN, HUMAN; SODIUM;

ADULT; ARTICLE; CARDIAC IMAGING; CARDIAC MUSCLE CELL; CLUSTERED REGULARLY INTERSPACED SHORT PALINDROMIC REPEAT; CONTROLLED STUDY; EMBRYO; FEMALE; FLUORESCENCE MICROSCOPY; GENE MUTATION; GENE SEQUENCE; GENETIC SCREENING; GENETIC VARIABILITY; HEART RIGHT VENTRICLE DYSPLASIA; HUMAN; HUMAN CELL; INDUCED PLURIPOTENT STEM CELL; MAJOR CLINICAL STUDY; MALE; MISSENSE MUTATION; MOLECULAR PATHOLOGY; MULTILEVEL ANALYSIS; PERIPHERAL BLOOD MONONUCLEAR CELL; PRIORITY JOURNAL; QRS INTERVAL; SODIUM CURRENT; WHOLE CELL PATCH CLAMP; WHOLE EXOME SEQUENCING; CELL DIFFERENTIATION; CLINICAL TRIAL; CRISPR CAS SYSTEM; DIAGNOSTIC IMAGING; DNA MUTATIONAL ANALYSIS; ELECTROCARDIOGRAPHY; EXOME; GENE EDITING; GENE FREQUENCY; GENETIC PREDISPOSITION; GENETIC TRANSFECTION; GENETICS; GENOME-WIDE ASSOCIATION STUDY; HEK293 CELL LINE; MEMBRANE POTENTIAL; METABOLISM; MIDDLE AGED; MULTICENTER STUDY; NETHERLANDS; NUCLEAR MAGNETIC RESONANCE IMAGING; PHENOTYPE; PROCEDURES; UNITED STATES; VALIDATION STUDY; YOUNG ADULT;

ADULT; ANTIGENS, CD; ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA; CADHERINS; CELL DIFFERENTIATION; CRISPR-CAS SYSTEMS; DNA MUTATIONAL ANALYSIS; ELECTROCARDIOGRAPHY; EXOME; FEMALE; GENE EDITING; GENE FREQUENCY; GENETIC PREDISPOSITION TO DISEASE; GENOME-WIDE ASSOCIATION STUDY; HEK293 CELLS; HUMANS; INDUCED PLURIPOTENT STEM CELLS; MAGNETIC RESONANCE IMAGING; MALE; MEMBRANE POTENTIALS; MIDDLE AGED; MULTILEVEL ANALYSIS; MUTATION, MISSENSE; MYOCYTES, CARDIAC; NAV1.5 VOLTAGE-GATED SODIUM CHANNEL; NETHERLANDS; PHENOTYPE; SODIUM; TRANSFECTION; UNITED STATES; YOUNG ADULT;

EID: 85016018479     PISSN: 00086363     EISSN: 17553245     Source Type: Journal    
DOI: 10.1093/cvr/cvw234     Document Type: Article

References (31)

1. Groeneweg JA, Bhonsale A, James CA, Te Riele AS, Dooijes D, Tichnell C, Murray B, Wiesfeld AC, Sawant AC, Kassamali B, Atsma DE, Volders PG, de Groot NM, de Boer K, Zimmerman SL, Kamel IR, van der Heijden JF, Russell SD, Cramer MJ, Tedford RJ, Doevendans PA, van Veen TA, Tandri H, Wilde AA, Judge DP, van Tintelen JP, Hauer RN, Calkins H. Clinical presentation, long-term follow-up, and outcomes of 1001 arrhythmogenic right ventricular dysplasia/cardiomyopathy patients and family members. Circ Cardiovasc Genet 2015;8:437-446.
2. Kaplan SR, Gard JJ, Protonotarios N, Tsatsopoulou A, Spiliopoulou C, Anastasakis A, Squarcioni CP, McKennaWJ, Thiene G, Basso C, Brousse N, Fontaine G, Saffitz JE. Remodeling of myocyte gap junctions in arrhythmogenic right ventricular cardiomyopathy due to a deletion in plakoglobin (naxos disease). Heart Rhythm 2004;1:3-11.
3. Cerrone M, Noorman M, Lin X, Chkourko H, Liang FX, van der Nagel R, Hund T, Birchmeier W, Mohler P, van Veen TA, van Rijen HV, Delmar M. Sodium current deficit and arrhythmogenesis in a murine model of plakophilin-2 haploinsufficiency. Cardiovasc Res 2012;95:460-468.
4. Noorman M, Hakim S, Asimaki A, Vreeker A, van Rijen HV, van der Heyden MA, de Jonge N, de Weger RA, Hauer RN, Saffitz JE, van Veen TA. Reduced plakoglobin immunoreactivity in arrhythmogenic cardiomyopathy: methodological considerations. Cardiovasc Pathol 2013;22:314-318.
5. Sato PY, Coombs W, Lin X, Nekrasova O, Green KJ, Isom LL, Taffet SM, Delmar M. Interactions between ankyrin-g, plakophilin-2, and connexin43 at the cardiac intercalated disc. Circ Res 2011;109:193-201.
6. Cerrone M, Lin X, Zhang M, Agullo-Pascual E, Pfenniger A, Chkourko Gusky H, Novelli V, Kim C, Tirasawadichai T, Judge DP, Rothenberg E, Chen HS, Napolitano C, Priori SG, Delmar M. Missense mutations in plakophilin-2 cause sodium current deficit and associate with a brugada syndrome phenotype. Circulation 2014;129:1092-1103.
7. Noorman M, Hakim S, Kessler E, Groeneweg JA, Cox MG, Asimaki A, van Rijen HV, van Stuijvenberg L, Chkourko H, van der Heyden MA, Vos MA, de Jonge N, van der Smagt JJ, Dooijes D, Vink A, de Weger RA, Varro A, de Bakker JM, Saffitz JE, Hund TJ, Mohler PJ, Delmar M, Hauer RN, van Veen TA. Remodeling of the cardiac sodium channel, connexin43, and plakoglobin at the intercalated disk in patients with arrhythmogenic cardiomyopathy. Heart Rhythm 2013;10:412-419.
8. Leo-Macias A, Agullo-Pascual E, Sanchez-Alonso JL, Keegan S, Lin X, Arcos T, Feng Xia L, Korchev YE, Gorelik J, Fenyo D, Rothenberg E, Rothenberg E, Delmar M. Nanoscale visualization of functional adhesion/excitability nodes at the intercalated disc. Nat Commun 2016;7:10342.
9. Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA, Calkins H, Corrado D, Cox MG, Daubert JP, Fontaine G, Gear K, Hauer R, Nava A, Picard MH, Protonotarios N, Saffitz JE, Sanborn DM, Steinberg JS, Tandri H, Thiene G, Towbin JA, Tsatsopoulou A, Wichter T, Zareba W. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria. Eur Heart J 2010;31:806-814.
10. UCSC Genome Browser. Accessible via https://genome.ucsc.edu (30 July 2016, date last accessed).
11. Bhonsale A, Groeneweg JA, James CA, Dooijes D, Tichnell C, Jongbloed JD, Murray B, Te Riele AS, van den Berg MP, Bikker H, Atsma DE, de Groot NM, Houweling AC, van der Heijden JF, Russell SD, Doevendans PA, van Veen TA, Tandri H, Wilde AA, Judge DP, van Tintelen JP, Calkins H, Hauer RN. Impact of genotype on clinical course in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated mutation carriers. Eur Heart J 2015;36:847-855.
12. Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F. Genome engineering using the crispr-cas9 system. Nat Protoc 2013;8:2281-2308.
13. Wang C, Hennessey JA, Kirkton RD, Wang C, Graham V, Puranam RS, Rosenberg PB, Bursac N, Pitt GS. Fibroblast growth factor homologous factor 13 regulates Na+ channels and conduction velocity in murine hearts. Circ Res 2011;109:775-782.
14. Weiss LA, Escayg A, Kearney JA, Trudeau M, MacDonald BT, Mori M, Reichert J, Buxbaum JD, Meisler MH. Sodium channels scn1a, scn2a and scn3a in familial autism. Mol Psychiatry 2003;8:186-194.
15. Wang C, Chung BC, Yan H, Wang HG, Lee SY, Pitt GS. Structural analyses of Ca(2)(+)/cam interaction with Nav channel c-termini reveal mechanisms of calciumdependent regulation. Nat Commun 2014;5:4896.
16. Olson TM, Keating MT. Mapping a cardiomyopathy locus to chromosome 3p22-p25. J Clin Invest 1996;97:528-532.
17. Olson TM, Michels VV, Ballew JD, Reyna SP, Karst ML, Herron KJ, Horton SC, Rodeheffer RJ, Anderson JL. Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. JAMA 2005;293:447-454.
18. Casini S, Tan HL, Demirayak I, Remme CA, Amin AS, Scicluna BP, Chatyan H, Ruijter JM, Bezzina CR, van Ginneken AC, Veldkamp MW. Tubulin polymerization modifies cardiac sodium channel expression and gating. Cardiovasc Res 2010;85:691-700.
19. Shaw RM, Fay AJ, Puthenveedu MA, von Zastrow M, Jan YN, Jan LY. Microtubule plus-end-tracking proteins target gap junctions directly from the cell interior to adherens junctions. Cell 2007;128:547-560.
20. Yu J, Hu J, Dai X, Cao Q, Xiong Q, Liu X, Liu X, Shen Y, Chen Q, Hua W, Hong K. Scn5a mutation in Chinese patients with arrhythmogenic right ventricular dysplasia. Herz 2014;39:271-275.
21. Rigato I, Bauce B, Rampazzo A, Zorzi A, Pilichou K, Mazzotti E, Migliore F, Marra MP, Lorenzon A, De Bortoli M, Calore M, Nava A, Daliento L, Gregori D, Iliceto S, Thiene G, Basso C, Corrado D. Compound and digenic heterozygosity predicts lifetime arrhythmic outcome and sudden cardiac death in desmosomal gene-related arrhythmogenic right ventricular cardiomyopathy. Circ Cardiovasc Genet 2013;6:533-542.
22. Kapplinger JD, Tester DJ, Alders M, Benito B, Berthet M, Brugada J, Brugada P, Fressart V, Guerchicoff A, Harris-Kerr C, Kamakura S, Kyndt F, Koopmann TT, Miyamoto Y, Pfeiffer R, Pollevick GD, Probst V, Zumhagen S, Vatta M, Towbin JA, Shimizu W, Schulze-Bahr E, Antzelevitch C, Salisbury BA, Guicheney P, Wilde AA, Brugada R, Schott JJ, Ackerman MJ. An international compendium of mutations in the scn5a-encoded cardiac sodium channel in patients referred for brugada syndrome genetic testing. Heart Rhythm 2010;7:33-46.
23. Postema PG, Van den Berg M, Van Tintelen JP, Van den Heuvel F, Grundeken M, Hofman N, Van der Roest WP, Nannenberg EA, Krapels IP, Bezzina CR, Wilde A. Founder mutations in the Netherlands: Scn5a 1795insd, the first described arrhythmia overlap syndrome and one of the largest and best characterised families worldwide. Neth Heart J 2009;17:422-428.
24. Le Scouarnec S, Karakachoff M, Gourraud JB, Lindenbaum P, Bonnaud S, Portero V, Duboscq-Bidot L, Daumy X, Simonet F, Teusan R, Baron E, Violleau J, Persyn E, Bellanger L, Barc J, Chatel S, Martins R, Mabo P, Sacher F, Haissaguerre M, Kyndt F, Schmitt S, Bezieau S, Le Marec H, Dina C, Schott JJ, Probst V, Redon R. Testing the burden of rare variation in arrhythmia-susceptibility genes provides new insights into molecular diagnosis for brugada syndrome. Hum Mol Genet 2015;24:2757-2763.
25. Ackerman MJ, Splawski I, Makielski JC, Tester DJ, Will ML, Timothy KW, Keating MT, Jones G, Chadha M, Burrow CR, Stephens JC, Xu C, Judson R, Curran ME. Spectrum and prevalence of cardiac sodium channel variants among Black, White, Asian, and Hispanic individuals: implications for arrhythmogenic susceptibility and brugada/long qt syndrome genetic testing. Heart Rhythm 2004;1:600-607.
26. Hu RM, Tan BH, Tester DJ, Song C, He Y, Dovat S, Peterson BZ, Ackerman MJ, Makielski JC. Arrhythmogenic biophysical phenotype for scn5a mutation s1787n depends upon splice variant background and intracellular acidosis. PLoS One 2015;10:e0124921.
27. Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL, Moss AJ, Schwartz PJ, Towbin JA, Vincent GM, Keating MT. Spectrum of mutations in long-qt syndrome genes. Kvlqt1, herg, scn5a, kcne1, and kcne2. Circulation 2000;102:1178-1185.
28. Chen J, Makiyama T, Wuriyanghai Y, Ohno S, Sasaki K, Hayano M, Harita T, Nishiuchi S, Yuta Y, Ueyama T, Shimizu A, Horie M, Kimura T. Cardiac sodium channel mutation associated with epinephrine-induced qt prolongation and sinus node dysfunction. Heart Rhythm 2016;13:289-298.
29. Shy D, Gillet L, Ogrodnik J, Albesa M, Verkerk AO, Wolswinkel R, Rougier JS, Barc J, Essers MC, Syam N, Marsman RF, van Mil AM, Rotman S, Redon R, Bezzina CR, Remme CA, Abriel H. Pdz domain-binding motif regulates cardiomyocyte compartment-specific nav1.5 channel expression and function. Circulation 2014;130:147-160.
30. Saguner AM, Ganahl S, Kraus A, Baldinger SH, Medeiros-Domingo A, Saguner AR, Mueller-Burri SA, Wolber T, Haegeli LM, Krasniqi N, Tanner FC, Steffel J, Brunckhorst C, Duru F. Clinical role of atrial arrhythmias in patients with arrhythmogenic right ventricular dysplasia. Circ J 2014;78:2854-2861.
31. Nagase S, Kusano KF, Morita H, Nishii N, Banba K, Watanabe A, Hiramatsu S, Nakamura K, Sakuragi S, Ohe T. Longer repolarization in the epicardium at the right ventricular outflow tract causes type 1 electrocardiogram in patients with brugada syndrome. J Am Coll Cardiol 2008;51:1154-1161.