Missense mutations in plakophilin-2 cause sodium current deficit and associate with a brugada syndrome phenotype

Circulation

Volumn 129, Issue 10, 2014, Pages 1092-1103

  Cerrone, Marina ^a   Lin, Xianming ^a   Zhang, Mingliang ^a   Agullo Pascual, Esperanza ^a   Pfenniger, Anna ^a   Chkourko Gusky, Halina ^a   Novelli, Valeria ^b   Kim, Changsung ^c,d   Tirasawadichai, Tiara ^c   Judge, Daniel P ^e   Rothenberg, Eli ^a   Chen, Huei Sheng Vincent ^c   Napolitano, Carlo ^b   Priori, Silvia G ^a,b   Delmar, Mario ^a  

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

^b IRCCS   (Italy)

^c BURNHAM INSTITUTE   (United States)

^d Sejong University   (South Korea)

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

Author keywords

Arrhythmogenic right ventricular dysplasia cardiomyopathy; Brugada syndrome; desmosomes; plakophilin 2; sodium channels

Indexed keywords

GENOMIC DNA; PLAKOPHILIN; PLAKOPHILIN 2; SODIUM CHANNEL; SODIUM CHANNEL NAV1.5; UNCLASSIFIED DRUG;

AMINO ACID SUBSTITUTION; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BRUGADA SYNDROME; CELL CONTACT; CONTROLLED STUDY; DISEASE ASSOCIATION; FEMALE; FLUORESCENCE MICROSCOPY; GENE; GENE LOSS; GENE MUTATION; GENETIC ASSOCIATION; GENETIC TRANSFECTION; GENETIC VARIABILITY; HEART MUSCLE CELL; HEART RIGHT VENTRICLE DYSPLASIA; HUMAN; MAJOR CLINICAL STUDY; MALE; MICROTUBULE; MISSENSE MUTATION; MOUSE; MURINAE; MUTANT; NONHUMAN; PHENOTYPE; PLURIPOTENT STEM CELL; PRIORITY JOURNAL; RETROSPECTIVE STUDY; SODIUM CHANNELOPATHY; SODIUM CURRENT; WILD TYPE;

ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA-CARDIOMYOPATHY; BRUGADA SYNDROME; DESMOSOMES; PLAKOPHILIN 2; SODIUM CHANNELS;

ADULT; ANIMALS; BRUGADA SYNDROME; CELL LINE; DISEASE MODELS, ANIMAL; FEMALE; GENOTYPE; HEART CONDUCTION SYSTEM; HUMANS; MALE; MICE; MICE, MUTANT STRAINS; MIDDLE AGED; MUTATION, MISSENSE; MYOCYTES, CARDIAC; NAV1.5 VOLTAGE-GATED SODIUM CHANNEL; PATCH-CLAMP TECHNIQUES; PEDIGREE; PHENOTYPE; PLAKOPHILINS; RETROSPECTIVE STUDIES; SODIUM CHANNELS;

EID: 84896749603     PISSN: 00097322     EISSN: 15244539     Source Type: Journal    
DOI: 10.1161/CIRCULATIONAHA.113.003077     Document Type: Article

References (38)

1. Van Tintelen JP, Entius MM, Bhuiyan ZA, Jongbloed R, Wiesfeld AC, Wilde AA, Van Der Smagt J, Boven LG, Mannens MM, Van Langen IM, Hofstra RM, Otterspoor LC, Doevendans PA, Rodriguez LM, Van Gelder IC, Hauer RN. Plakophilin-2 mutations are the major determinant of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circulation. 2006;113:1650-1658.
2. Oxford EM, Musa H, Maass K, Coombs W, Taffet SM, Delmar M. Connexin43 remodeling caused by inhibition of plakophilin-2 expression in cardiac cells. Circ Res. 2007;101:703-711.
3. Agullo-Pascual E, Reid DA, Keegan S, Sidhu M, Feny D, Rothenberg E, Delmar M. Super-resolution fluorescence microscopy of the cardiac connexome reveals plakophilin-2 inside the connexin43 plaque. Cardiovasc Res. 2013;100:231-240.
4. 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.
5. Sato PY, Musa H, Coombs W, Guerrero-Serna G, Patio GA, Taffet SM, Isom LL, Delmar M. Loss of plakophilin-2 expression leads to decreased sodium current and slower conduction velocity in cultured cardiac myocytes. Circ Res. 2009;105:523-526.
6. 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.
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. Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, Potenza D, Moya A, Borggrefe M, Breithardt G, Ortiz-Lopez R, Wang Z, Antzelevitch C, OBrien RE, Schulze-Bahr E, Keating MT, Towbin JA, Wang Q. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature. 1998;392:293-296.
9. Bhargava A, Lin X, Novak P, Mehta K, Korchev Y, Delmar M, Gorelik J. Super-resolution scanning patch clamp reveals clustering of functional ion channels in adult ventricular myocyte. Circ Res. 2013;112:1112-1120.
10. Claycomb WC, Lanson NA Jr, Stallworth BS, Egeland DB, Delcarpio JB, Bahinski A, Izzo NJ Jr. HL-1 cells: A cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte. Proc Natl Acad Sci U S A. 1998;95:2979-2984.
11. Chkourko HS, Guerrero-Serna G, Lin X, Darwish N, Pohlmann JR, Cook KE, Martens JR, Rothenberg E, Musa H, Delmar M. Remodeling of mechanical junctions and of microtubule-associated proteins accompany cardiac connexin43 lateralization. Heart Rhythm. 2012;9 :1133-1140.e6.
12. Kim C, Wong J, Wen J, Wang S, Wang C, Spiering S, Kan NG, Forcales S, Puri PL, Leone TC, Marine JE, Calkins H, Kelly DP, Judge DP, Chen HS. Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs. Nature. 2013;494:105-110.
13. Awad MM, Dalal D, Tichnell C, James C, Tucker A, Abraham T, Spevak PJ, Calkins H, Judge DP. Recessive arrhythmogenic right ventricular dysplasia due to novel cryptic splice mutation in PKP2. Hum Mutat. 2006;27:1157.
14. Norton N, Robertson PD, Rieder MJ, Zchner S, Rampersaud E, Martin E, Li D, Nickerson DA, Hershberger RE; National Heart, Lung and Blood Institute GO Exome Sequencing Project. Evaluating pathogenicity of rare variants from dilated cardiomyopathy in the exome era. Circ Cardiovasc Genet. 2012;5:167-174.
15. Van Der Zwaag PA, Jongbloed JD, Van Den Berg MP, Van Der Smagt JJ, Jongbloed R, Bikker H, Hofstra RM, Van Tintelen JP. A genetic variants database for arrhythmogenic right ventricular dysplasia/cardiomyopathy. Hum Mutat. 2009;30:1278-1283.
16. Christensen AH, Benn M, Bundgaard H, Tybjaerg-Hansen A, Haunso S, Svendsen JH. Wide spectrum of desmosomal mutations in Danish patients with arrhythmogenic right ventricular cardiomyopathy. J Med Genet. 2010;47:736-744.
17. Bauce B, Nava A, Beffagna G, Basso C, Lorenzon A, Smaniotto G, De Bortoli M, Rigato I, Mazzotti E, Steriotis A, Marra MP, Towbin JA, Thiene G, Danieli GA, Rampazzo A. Multiple mutations in desmosomal proteins encoding genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia. Heart Rhythm. 2010;7:22-29.
18. Lahtinen AM, Lehtonen E, Marjamaa A, Kaartinen M, Heli T, Porthan K, Oikarinen L, Toivonen L, Swan H, Jula A, Peltonen L, Palotie A, Salomaa V, Kontula K. Population-prevalent desmosomal mutations predisposing to arrhythmogenic right ventricular cardiomyopathy. Heart Rhythm. 2011;8:1214-1221.
19. Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, Gussak I, LeMarec H, Nademanee K, Perez Riera AR, Shimizu W, Schulze-Bahr E, Tan H, Wilde A. Brugada syndrome: Report of the second consensus conference: Endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation. 2005;111:659-670.
20. Mao W, You T, Ye B, Li X, Dong HH, Hill JA, Li F, Xu H. Reactive oxygen species suppress cardiac NaV1.5 expression through Foxo1. PLoS One. 2012;7:e32738.
21. Lin X, Liu N, Lu J, Zhang J, Anumonwo JM, Isom LL, Fishman GI, Delmar M. Subcellular heterogeneity of sodium current properties in adult cardiac ventricular myocytes. Heart Rhythm. 2011;8:1923-1930.
22. Lbkemeier I, Requardt RP, Lin X, Sasse P, Andri R, Schrickel JW, Chkourko H, Bukauskas FF, Kim JS, Frank M, Malan D, Zhang J, Wirth A, Dobrowolski R, Mohler PJ, Offermanns S, Fleischmann BK, Delmar M, Willecke K. Deletion of the last five C-terminal amino acid residues of connexin43 leads to lethal ventricular arrhythmias in mice without affecting coupling via gap junction channels. Basic Res Cardiol. 2013;108:348.
23. 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.
24. OBrien JE, Sharkey LM, Vallianatos CN, Han C, Blossom JC, Yu T, Waxman SG, Dib-Hajj SD, Meisler MH. Interaction of voltage-gated sodium channel Nav1.6 (SCN8A) with microtubule-associated protein Map1b. J Biol Chem. 2012;287:18459-18466.
25. 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.
26. Rizzo S, Lodder EM, Verkerk AO, Wolswinkel R, Beekman L, Pilichou K, Basso C, Remme CA, Thiene G, Bezzina CR. Intercalated disc abnormalities, reduced Na(+) current density, and conduction slowing in desmoglein-2 mutant mice prior to cardiomyopathic changes. Cardiovasc Res. 2012;95:409-418.
27. Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, Camm AJ, Ellinor PT, Gollob M, Hamilton R, Hershberger RE, Judge DP, Le Marec H, McKenna WJ, Schulze-Bahr E, Semsarian C, Towbin JA, Watkins H, Wilde A, Wolpert C, Zipes DP. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm. 2011;8:1308-1339.
28. Corrado D, Basso C, Buja G, Nava A, Rossi L, Thiene G. Right bundle branch block, right precordial st-segment elevation, and sudden death in young people. Circulation. 2001;103:710-717.
29. Catalano O, Antonaci S, Moro G, Mussida M, Frascaroli M, Baldi M, Cobelli F, Baiardi P, Nastoli J, Bloise R, Monteforte N, Napolitano C, Priori SG. Magnetic resonance investigations in Brugada syndrome reveal unexpectedly high rate of structural abnormalities. Eur Heart J. 2009;30:2241-2248.
30. Gerull B, Heuser A, Wichter T, Paul M, Basson CT, McDermott DA, Lerman BB, Markowitz SM, Ellinor PT, MacRae CA, Peters S, Grossmann KS, Drenckhahn J, Michely B, Sasse-Klaassen S, Birchmeier W, Dietz R, Breithardt G, Schulze-Bahr E, Thierfelder L. Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet. 2004;36:1162-1164.
31. Zhang M, Tavora F, Oliveira JB, Li L, Franco M, Fowler D, Zhao Z, Burke A. PKP2 mutations in sudden death from arrhythmogenic right ventricular cardiomyopathy (ARVC) and sudden unexpected death with negative autopsy (SUDNA). Circ J. 2012;76:189-194.
32. Gomes J, Finlay M, Ahmed AK, Ciaccio EJ, Asimaki A, Saffitz JE, Quarta G, Nobles M, Syrris P, Chaubey S, McKenna WJ, Tinker A, Lambiase PD. Electrophysiological abnormalities precede overt structural changes in arrhythmogenic right ventricular cardiomyopathy due to mutations in desmoplakin-A combined murine and human study. Eur Heart J. 2012;33:1942-1953.
33. Kaplan SR, Gard JJ, Protonotarios N, Tsatsopoulou A, Spiliopoulou C, Anastasakis A, Squarcioni CP, McKenna WJ, 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.
34. Ruan Y, Liu N, Priori SG. Sodium channel mutations and arrhythmias. Nat Rev Cardiol. 2009;6:337-348.
35. Cerrone M, Napolitano C, Priori SG. Genetics of ion-channel disorders. Curr Opin Cardiol. 2012;27:242-252.
36. Morimoto S. Sarcomeric proteins and inherited cardiomyopathies. Cardiovasc Res. 2008;77:659-666.
37. Van Hengel J, Calore M, Bauce B, Dazzo E, Mazzotti E, De Bortoli M, Lorenzon A, Li Mura IE, Beffagna G, Rigato I, Vleeschouwers M, Tyberghein K, Hulpiau P, Van Hamme E, Zaglia T, Corrado D, Basso C, Thiene G, Daliento L, Nava A, Van Roy F, Rampazzo A. Mutations in the area composita protein T-catenin are associated with arrhythmogenic right ventricular cardiomyopathy. Eur Heart J. 2013;34:201-210.
38. Rhett JM, Gourdie RG. The perinexus: A new feature of Cx43 gap junction organization. Heart Rhythm. 2012;9:619-623.