Skip to main content
SpringerLink
Log in

Genetics of and pathogenic mechanisms in arrhythmogenic right ventricular cardiomyopathy

  • Review
  • Published:
Biophysical Reviews Aims and scope Submit manuscript

Abstract

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease, associated with a high risk of sudden cardiac death. ARVC has been termed a ‘disease of the desmosome’ based on the fact that in many cases, it is caused by mutations in genes encoding desmosomal proteins at the specialised intercellular junctions between cardiomyocytes, the intercalated discs. Desmosomes maintain the structural integrity of the ventricular myocardium and are also implicated in signal transduction pathways. Mutated desmosomal proteins are thought to cause detachment of cardiac myocytes by the loss of cellular adhesions and also affect signalling pathways, leading to cell death and substitution by fibrofatty adipocytic tissue. However, mutations in desmosomal proteins are not the sole cause for ARVC as mutations in non-desmosomal genes were also implicated in its pathogenesis. This review will consider the pathology, genetic basis and mechanisms of pathogenesis for ARVC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Al-Jassar C, Bikker H, Overduin M, Chidgey M (2013) Mechanistic basis of desmosome-targeted diseases. J Mol Biol 425:4006–4022

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Andreasen C, Nielsen JB, Refsgaard L, Holst AG, Christensen AH, Andreasen L, Sajadieh A, Haunso S, Svendsen JH, Olesen MS (2013) New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants. Eur J Hum Genet 21:918–928

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Asimaki A, Syrris P, Wichter T, Matthias P, Saffitz JE, McKenna WJ (2007) A novel dominant mutation in plakoglobin causes arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet 81:964–973

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Asimaki A, Tandri H, Huang H, Halushka MK, Gautam S, Basso C, Thiene G, Tsatsopoulou A, Protonotarios N, McKenna WJ, Calkins H, Saffitz JE (2009) A new diagnostic test for arrhythmogenic right ventricular cardiomyopathy. N Engl J Med 360:1075–1084

    Article  PubMed  CAS  Google Scholar 

  • Asimaki A, Kapoor S, Plovie E, Karin Arndt A, Adams E, Liu Z, James CA, Judge DP, Calkins H, Churko J, Wu JC, MacRae CA, Kleber AG, Saffitz JE (2014) Identification of a new modulator of the intercalated disc in a zebrafish model of arrhythmogenic cardiomyopathy. Sci Transl Med 6:240ra74

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Awad MM, Dalal D, Cho E, Amat-Alarcon N, James C, Tichnell C, Tucker A, Russell SD, Bluemke DA, Dietz HC, Calkins H, Judge DP (2006) DSG2 mutations contribute to arrhythmogenic right ventricular dysplasia/cardiomyopathy. Am J Hum Genet 79:136–142

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Basso C, Thiene G, Corrado D, Angelini A, Nava A, Valente M (1996) Arrhythmogenic right ventricular cardiomyopathy. Dysplasia, dystrophy, or myocarditis? Circulation 94:983–991

    Article  PubMed  CAS  Google Scholar 

  • Basso C, Pilichou K, Bauce B, Corrado D, Thiene G (2018) Diagnostic criteria, genetics, and molecular basis of arrhythmogenic cardiomyopathy. Heart Fail Clin 14:201–213

    Article  PubMed  Google Scholar 

  • Beffagna G, Occhi G, Nava A, Vitiello L, Ditadi A, Basso C, Bauce B, Carraro G, Thiene G, Towbin JA, Danieli GA, Rampazzo A (2005) Regulatory mutations in transforming growth factor-beta3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1. Cardiovasc Res 65:366–373

    Article  PubMed  CAS  Google Scholar 

  • Beffagna G, De Bortoli M, Nava A, Salamon M, Lorenzon A, Zaccolo M, Mancuso L, Sigalotti L, Bauce B, Occhi G, Basso C, Lanfranchi G, Towbin JA, Thiene G, Danieli GA, Rampazzo A (2007) Missense mutations in desmocollin-2 N-terminus, associated with arrhythmogenic right ventricular cardiomyopathy, affect intracellular localization of desmocollin-2 in vitro. BMC Med Genet 8:65

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Broussard JA, Getsios S, Green KJ (2015) Desmosome regulation and signaling in disease. Cell Tissue Res 360:501–512

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Campuzano O, Alcalde M, Iglesias A, Barahona-Dussault C, Sarquella-Brugada G, Benito B, Arzamendi D, Flores J, Leung TK, Talajic M, Oliva A, Brugada R (2012) Arrhythmogenic right ventricular cardiomyopathy: severe structural alterations are associated with inflammation. J Clin Pathol 65:1077–1083

    Article  PubMed  Google Scholar 

  • Castelletti S, Vischer AS, Syrris P, Crotti L, Spazzolini C, Ghidoni A, Parati G, Jenkins S, Kotta MC, McKenna WJ, Schwartz PJ, Pantazis A (2017) Desmoplakin missense and non-missense mutations in arrhythmogenic right ventricular cardiomyopathy: genotype-phenotype correlation. Int J Cardiol 249:268–273

    Article  PubMed  Google Scholar 

  • 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 (2012) Sodium current deficit and arrhythmogenesis in a murine model of plakophilin-2 haploinsufficiency. Cardiovasc Res 95:460–468

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cerrone M, Montnach J, Lin X, Zhao YT, Zhang M, Agullo-Pascual E, Leo-Macias A, Alvarado FJ, Dolgalev I, Karathanos TV, Malkani K, Van Opbergen CJM, van Bavel JJA, Yang HQ, Vasquez C, Tester D, Fowler S, Liang F, Rothenberg E, Heguy A, Morley GE, Coetzee WA, Trayanova NA, Ackerman MJ, van Veen TAB, Valdivia HH, Delmar M (2017) Plakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm. Nat Commun 8:106

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chelko SP, Asimaki A, Andersen P, Bedja D, Amat-Alarcon N, DeMazumder D, Jasti R, MacRae CA, Leber R, Kleber AG, Saffitz JE, Judge DP (2016) Central role for GSK3beta in the pathogenesis of arrhythmogenic cardiomyopathy. JCI Insight 1

  • Chen SN, Gurha P, Lombardi R, Ruggiero A, Willerson JT, Marian AJ (2014) The hippo pathway is activated and is a causal mechanism for adipogenesis in arrhythmogenic cardiomyopathy. Circ Res 114:454–468

    Article  PubMed  CAS  Google Scholar 

  • Chopra A, Tabdanov E, Patel H, Janmey PA, Kresh JY (2011) Cardiac myocyte remodeling mediated by N-cadherin-dependent mechanosensing. Am J Physiol Heart Circ Physiol 300:H1252–H1266

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Corrado D, Basso C, Judge DP (2017) Arrhythmogenic cardiomyopathy. Circ Res 121:784–802

    Article  PubMed  CAS  Google Scholar 

  • Dalal D, Molin LH, Piccini J, Tichnell C, James C, Bomma C, Prakasa K, Towbin JA, Marcus FI, Spevak PJ, Bluemke DA, Abraham T, Russell SD, Calkins H, Judge DP (2006) Clinical features of arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in plakophilin-2. Circulation 113:1641–1649

    Article  PubMed  CAS  Google Scholar 

  • De Bortoli M, Beffagna G, Bauce B, Lorenzon A, Smaniotto G, Rigato I, Calore M, Li Mura IE, Basso C, Thiene G, Lanfranchi G, Danieli GA, Nava A, Rampazzo A (2010) The p.A897KfsX4 frameshift variation in desmocollin-2 is not a causative mutation in arrhythmogenic right ventricular cardiomyopathy. Eur J Hum Genet 18:776–782

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dieding M, Debus JD, Kerkhoff R, Gaertner-Rommel A, Walhorn V, Milting H, Anselmetti D (2017) Arrhythmogenic cardiomyopathy related DSG2 mutations affect desmosomal cadherin binding kinetics. Sci Rep 7:13791

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dubash AD, Kam CY, Aguado BA, Patel DM, Delmar M, Shea LD, Green KJ (2016) Plakophilin-2 loss promotes TGF-beta1/p38 MAPK-dependent fibrotic gene expression in cardiomyocytes. J Cell Biol 212:425–438

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Franke WW, Borrmann CM, Grund C, Pieperhoff S (2006) The area composita of adhering junctions connecting heart muscle cells of vertebrates. I. Molecular definition in intercalated disks of cardiomyocytes by immunoelectron microscopy of desmosomal proteins. Eur J Cell Biol 85:69–82

    Article  PubMed  CAS  Google Scholar 

  • Garcia-Gras E, Lombardi R, Giocondo MJ, Willerson JT, Schneider MD, Khoury DS, Marian AJ (2006) Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy. J Clin Invest 116:2012–2021

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gehmlich K, Lambiase PD, Asimaki A, Ciaccio EJ, Ehler E, Syrris P, Saffitz JE, McKenna WJ (2011a) A novel desmocollin-2 mutation reveals insights into the molecular link between desmosomes and gap junctions. Heart Rhythm 8:711–718

    Article  PubMed  PubMed Central  Google Scholar 

  • Gehmlich K, Syrris P, Peskett E, Evans A, Ehler E, Asimaki A, Anastasakis A, Tsatsopoulou A, Vouliotis AI, Stefanadis C, Saffitz JE, Protonotarios N, McKenna WJ (2011b) Mechanistic insights into arrhythmogenic right ventricular cardiomyopathy caused by desmocollin-2 mutations. Cardiovasc Res 90:77–87

    Article  PubMed  CAS  Google Scholar 

  • 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 (2004) Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet 36:1162–1164

    Article  PubMed  CAS  Google Scholar 

  • Hall C, Li S, Li H, Creason V, Wahl JK 3rd (2009) Arrhythmogenic right ventricular cardiomyopathy plakophilin-2 mutations disrupt desmosome assembly and stability. Cell Commun Adhes 16:15–27

    Article  PubMed  CAS  Google Scholar 

  • Herren T, Gerber PA, Duru F (2009) Arrhythmogenic right ventricular cardiomyopathy/dysplasia: a not so rare “disease of the desmosome” with multiple clinical presentations. Clin Res Cardiol 98:141–158

    Article  PubMed  Google Scholar 

  • Huang NN, Becker S, Boularan C, Kamenyeva O, Vural A, Hwang IY, Shi CS, Kehrl JH (2014) Canonical and noncanonical g-protein signaling helps coordinate actin dynamics to promote macrophage phagocytosis of zymosan. Mol Cell Biol 34:4186–4199

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kant S, Krusche CA, Gaertner A, Milting H, Leube RE (2016) Loss of plakoglobin immunoreactivity in intercalated discs in arrhythmogenic right ventricular cardiomyopathy: protein mislocalization versus epitope masking. Cardiovasc Res 109:260–271

    Article  PubMed  CAS  Google Scholar 

  • Kelly RG, Buckingham ME, Moorman AF (2014) Heart fields and cardiac morphogenesis. Cold Spring Harb Perspect Med 4

  • Kottke MD, Delva E, Kowalczyk AP (2006) The desmosome: cell science lessons from human diseases. J Cell Sci 119:797–806

    Article  PubMed  CAS  Google Scholar 

  • Laitinen PJ, Brown KM, Piippo K, Swan H, Devaney JM, Brahmbhatt B, Donarum EA, Marino M, Tiso N, Viitasalo M, Toivonen L, Stephan DA, Kontula K (2001) Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia. Circulation 103:485–490

    Article  PubMed  CAS  Google Scholar 

  • Lazzarini E, Jongbloed JD, Pilichou K, Thiene G, Basso C, Bikker H, Charbon B, Swertz M, van Tintelen JP, van der Zwaag PA (2015) The ARVD/C genetic variants database: 2014 update. Hum Mutat 36:403–410

    Article  PubMed  CAS  Google Scholar 

  • Lehnart SE, Mongillo M, Bellinger A, Lindegger N, Chen BX, Hsueh W, Reiken S, Wronska A, Drew LJ, Ward CW, Lederer WJ, Kass RS, Morley G, Marks AR (2008) Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice. J Clin Invest 118:2230–2245

    PubMed  PubMed Central  CAS  Google Scholar 

  • Lombardi R, Marian AJ (2010) Arrhythmogenic right ventricular cardiomyopathy is a disease of cardiac stem cells. Curr Opin Cardiol 25:222–228

    Article  PubMed  PubMed Central  Google Scholar 

  • Lopez-Ayala JM, Gomez-Milanes I, Sanchez Munoz JJ, Ruiz-Espejo F, Ortiz M, Gonzalez-Carrillo J, Lopez-Cuenca D, Oliva-Sandoval MJ, Monserrat L, Valdes M, Gimeno JR (2014) Desmoplakin truncations and arrhythmogenic left ventricular cardiomyopathy: characterizing a phenotype. Europace 16:1838–1846

    Article  PubMed  Google Scholar 

  • Mallat Z, Tedgui A, Fontaliran F, Frank R, Durigon M, Fontaine G (1996) Evidence of apoptosis in arrhythmogenic right ventricular dysplasia. N Engl J Med 335:1190–1196

    Article  PubMed  CAS  Google Scholar 

  • Marcus FI, Fontaine GH, Guiraudon G, Frank R, Laurenceau JL, Malergue C, Grosgogeat Y (1982) Right ventricular dysplasia: a report of 24 adult cases. Circulation 65:384–398

    Article  PubMed  CAS  Google Scholar 

  • 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 (2010) Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria. Circulation 121:1533–1541

    Article  PubMed  PubMed Central  Google Scholar 

  • Matsumori A, Kawai C (1980) Coxsackie virus B3 perimyocarditis in BALB/c mice: experimental model of chronic perimyocarditis in the right ventricle. J Pathol 131:97–106

    Article  PubMed  CAS  Google Scholar 

  • Mayosi BM, Fish M, Shaboodien G, Mastantuono E, Kraus S, Wieland T, Kotta MC, Chin A, Laing N, Ntusi NB, Chong M, Horsfall C, Pimstone SN, Gentilini D, Parati G, Strom TM, Meitinger T, Pare G, Schwartz PJ, Crotti L (2017) Identification of cadherin 2 (CDH2) mutations in arrhythmogenic right ventricular cardiomyopathy. Circ Cardiovasc Genet 10

  • McKoy G, Protonotarios N, Crosby A, Tsatsopoulou A, Anastasakis A, Coonar A, Norman M, Baboonian C, Jeffery S, McKenna WJ (2000) Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet 355:2119–2124

    Article  PubMed  CAS  Google Scholar 

  • Merner ND, Hodgkinson KA, Haywood AF, Connors S, French VM, Drenckhahn JD, Kupprion C, Ramadanova K, Thierfelder L, McKenna W, Gallagher B, Morris-Larkin L, Bassett AS, Parfrey PS, Young TL (2008) Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene. Am J Hum Genet 82:809–821

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mertens C, Kuhn C, Franke WW (1996) Plakophilins 2a and 2b: constitutive proteins of dual location in the karyoplasm and the desmosomal plaque. J Cell Biol 135:1009–1025

    Article  PubMed  CAS  Google Scholar 

  • Nava A, Thiene G, Canciani B, Scognamiglio R, Daliento L, Buja G, Martini B, Stritoni P, Fasoli G (1988) Familial occurrence of right ventricular dysplasia: a study involving nine families. J Am Coll Cardiol 12:1222–1228

    Article  PubMed  CAS  Google Scholar 

  • 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 (2013) Remodeling of the cardiac sodium channel, connexin43, and plakoglobin at the intercalated disk in patients with arrhythmogenic cardiomyopathy. Heart Rhythm 10:412–419

    Article  PubMed  Google Scholar 

  • Norgett EE, Hatsell SJ, Carvajal-Huerta L, Cabezas JC, Common J, Purkis PE, Whittock N, Leigh IM, Stevens HP, Kelsell DP (2000) Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Hum Mol Genet 9:2761–2766

    Article  PubMed  CAS  Google Scholar 

  • Pilichou K, Nava A, Basso C, Beffagna G, Bauce B, Lorenzon A, Frigo G, Vettori A, Valente M, Towbin J, Thiene G, Danieli GA, Rampazzo A (2006) Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy. Circulation 113:1171–1179

    Article  PubMed  CAS  Google Scholar 

  • Pilichou K, Remme CA, Basso C, Campian ME, Rizzo S, Barnett P, Scicluna BP, Bauce B, van den Hoff MJ, de Bakker JM, Tan HL, Valente M, Nava A, Wilde AA, Moorman AF, Thiene G, Bezzina CR (2009) Myocyte necrosis underlies progressive myocardial dystrophy in mouse dsg2-related arrhythmogenic right ventricular cardiomyopathy. J Exp Med 206:1787–1802

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pilichou K, Thiene G, Bauce B, Rigato I, Lazzarini E, Migliore F, Perazzolo Marra M, Rizzo S, Zorzi A, Daliento L, Corrado D, Basso C (2016) Arrhythmogenic cardiomyopathy. Orphanet J Rare Dis 11:33

    Article  PubMed  PubMed Central  Google Scholar 

  • Protonotarios N, Tsatsopoulou A (2004) Naxos disease and Carvajal syndrome: cardiocutaneous disorders that highlight the pathogenesis and broaden the spectrum of arrhythmogenic right ventricular cardiomyopathy. Cardiovasc Pathol 13:185–194

    Article  PubMed  CAS  Google Scholar 

  • Quarta G, Syrris P, Ashworth M, Jenkins S, Zuborne Alapi K, Morgan J, Muir A, Pantazis A, McKenna WJ, Elliott PM (2012) Mutations in the Lamin a/C gene mimic arrhythmogenic right ventricular cardiomyopathy. Eur Heart J 33:1128–1136

    Article  PubMed  CAS  Google Scholar 

  • Rampazzo A, Nava A, Danieli GA, Buja G, Daliento L, Fasoli G, Scognamiglio R, Corrado D, Thiene G (1994) The gene for arrhythmogenic right ventricular cardiomyopathy maps to chromosome 14q23-q24. Hum Mol Genet 3:959–962

    Article  PubMed  CAS  Google Scholar 

  • Rampazzo A, Nava A, Malacrida S, Beffagna G, Bauce B, Rossi V, Zimbello R, Simionati B, Basso C, Thiene G, Towbin JA, Danieli GA (2002) Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet 71:1200–1206

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sato PY, Coombs W, Lin X, Nekrasova O, Green KJ, Isom LL, Taffet SM, Delmar M (2011) Interactions between ankyrin-G, plakophilin-2, and connexin43 at the cardiac intercalated disc. Circ Res 109:193–201

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sen-Chowdhry S, Syrris P, McKenna WJ (2005) Genetics of right ventricular cardiomyopathy. J Cardiovasc Electrophysiol 16:927–935

    Article  PubMed  Google Scholar 

  • Shen WK, Edwards WD, Hammill SC, Bailey KR, Ballard DJ, Gersh BJ (1995) Sudden unexpected nontraumatic death in 54 young adults: a 30-year population-based study. Am J Cardiol 76:148–152

    Article  PubMed  CAS  Google Scholar 

  • Soonpaa MH, Kim KK, Pajak L, Franklin M, Field LJ (1996) Cardiomyocyte DNA synthesis and binucleation during murine development. Am J Phys 271:H2183–H2189

    CAS  Google Scholar 

  • Sporn MB, Roberts AB (1992) Transforming growth factor-beta: recent progress and new challenges. J Cell Biol 119:1017–1021

    Article  PubMed  CAS  Google Scholar 

  • Stokoe KS, Thomas G, Goddard CA, Colledge WH, Grace AA, Huang CL (2007) Effects of flecainide and quinidine on arrhythmogenic properties of Scn5a+/Delta murine hearts modelling long QT syndrome 3. J Physiol 578:69–84

    Article  PubMed  CAS  Google Scholar 

  • Stroud MJ, Fang X, Zhang J, Guimaraes-Camboa N, Veevers J, Dalton ND, Gu Y, Bradford WH, Peterson KL, Evans SM, Gerace L, Chen J (2018) Luma is not essential for murine cardiac development and function. Cardiovasc Res 114:378–388

    Article  PubMed  Google Scholar 

  • Syrris P, Ward D, Evans A, Asimaki A, Gandjbakhch E, Sen-Chowdhry S, McKenna WJ (2006) Arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in the desmosomal gene desmocollin-2. Am J Hum Genet 79:978–984

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Taylor M, Graw S, Sinagra G, Barnes C, Slavov D, Brun F, Pinamonti B, Salcedo EE, Sauer W, Pyxaras S, Anderson B, Simon B, Bogomolovas J, Labeit S, Granzier H, Mestroni L (2011) Genetic variation in titin in arrhythmogenic right ventricular cardiomyopathy-overlap syndromes. Circulation 124:876–885

    Article  PubMed  PubMed Central  Google Scholar 

  • Te Riele AS, Agullo-Pascual E, James CA, Leo-Macias A, Cerrone M, Zhang M, Lin X, Lin B, Sobreira NL, Amat-Alarcon N, Marsman RF, Murray B, Tichnell C, van der Heijden JF, Dooijes D, van Veen TA, Tandri H, Fowler SJ, Hauer RN, Tomaselli G, van den Berg MP, Taylor MR, Brun F, Sinagra G, Wilde AA, Mestroni L, Bezzina CR, Calkins H, Peter van Tintelen J, Bu L, Delmar M, Judge DP (2017) Multilevel analyses of SCN5A mutations in arrhythmogenic right ventricular dysplasia/cardiomyopathy suggest non-canonical mechanisms for disease pathogenesis. Cardiovasc Res 113:102–111

    Article  CAS  Google Scholar 

  • Thiene G, Corrado D, Nava A, Rossi L, Poletti A, Boffa GM, Daliento L, Pennelli N (1991) Right ventricular cardiomyopathy: is there evidence of an inflammatory aetiology? Eur Heart J 12(Suppl D):22–25

    Article  PubMed  Google Scholar 

  • Thiene G, Basso C, Angelini A, Calabrese F, Valente M (1998) Morbid anatomy and pathobiology of arrhythmogenic right ventricular cardiomyopathy. Herzschrittmacherther Elektrophysiol 9:147–154

    Article  Google Scholar 

  • Thiene G, Basso C, Calabrese F, Angelini A, Valente M (2000) Pathology and pathogenesis of arrhythmogenic right ventricular cardiomyopathy. Herz 25:210–215

    Article  PubMed  CAS  Google Scholar 

  • Tiso N, Stephan DA, Nava A, Bagattin A, Devaney JM, Stanchi F, Larderet G, Brahmbhatt B, Brown K, Bauce B, Muriago M, Basso C, Thiene G, Danieli GA, Rampazzo A (2001) Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Hum Mol Genet 10:189–194

    Article  PubMed  CAS  Google Scholar 

  • van der Zwaag PA, van Rijsingen IA, Asimaki A, Jongbloed JD, van Veldhuisen DJ, Wiesfeld AC, Cox MG, van Lochem LT, de Boer RA, Hofstra RM, Christiaans I, van Spaendonck-Zwarts KY, Lekanne dit Deprez RH, Judge DP, Calkins H, Suurmeijer AJ, Hauer RN, Saffitz JE, Wilde AA, van den Berg MP, van Tintelen JP (2012) Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy. Eur J Heart Fail 14:1199–1207

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 (2013) Mutations in the area composita protein alphaT-catenin are associated with arrhythmogenic right ventricular cardiomyopathy. Eur Heart J 34:201–210

    Article  PubMed  CAS  Google Scholar 

  • van Tintelen JP, Van Gelder IC, Asimaki A, Suurmeijer AJ, Wiesfeld AC, Jongbloed JD, van den Wijngaard A, Kuks JB, van Spaendonck-Zwarts KY, Notermans N, Boven L, van den Heuvel F, Veenstra-Knol HE, Saffitz JE, Hofstra RM, van den Berg MP (2009) Severe cardiac phenotype with right ventricular predominance in a large cohort of patients with a single missense mutation in the DES gene. Heart Rhythm 6:1574–1583

    Article  PubMed  Google Scholar 

  • Vatta M, Marcus F, Towbin JA (2007) Arrhythmogenic right ventricular cardiomyopathy: a 'final common pathway' that defines clinical phenotype. Eur Heart J 28:529–530

    Article  PubMed  CAS  Google Scholar 

  • Vermij SH, Abriel H, van Veen TA (2017) Refining the molecular organization of the cardiac intercalated disc. Cardiovasc Res 113:259–275

    Article  PubMed  Google Scholar 

  • Xu T, Yang Z, Vatta M, Rampazzo A, Beffagna G, Pilichou K, Scherer SE, Saffitz J, Kravitz J, Zareba W, Danieli GA, Lorenzon A, Nava A, Bauce B, Thiene G, Basso C, Calkins H, Gear K, Marcus F, Towbin JA, Multidisciplinary Study of Right Ventricular Dysplasia I (2010) Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol 55:587–597

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ye X, Zhang HM, Qiu Y, Hanson PJ, Hemida MG, Wei W, Hoodless PA, Chu F, Yang D (2014) Coxsackievirus-induced miR-21 disrupts cardiomyocyte interactions via the downregulation of intercalated disk components. PLoS Pathog 10:e1004070

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yu FX, Guan KL (2013) The hippo pathway: regulators and regulations. Genes Dev 27:355–371

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhou L, Hanemann CO (2012) Merlin, a multi-suppressor from cell membrane to the nucleus. FEBS Lett 586:1403–1408

    Article  PubMed  CAS  Google Scholar 

  • Zhurinsky J, Shtutman M, Ben-Ze'ev A (2000) Differential mechanisms of LEF/TCF family-dependent transcriptional activation by beta-catenin and plakoglobin. Mol Cell Biol 20:4238–4252

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Randall Centre for Cell and Molecular Biophysics, School of Basic and Medical Biosciences, London, UK

    Anita Kiran Vimalanathan & Elisabeth Ehler

  2. School of Cardiovascular Medicine and Sciences, British Heart Foundation Research Excellence Centre, King’s College London, London, UK

    Elisabeth Ehler

  3. Division of Cardiovascular Medicine, Radcliffe Department of Medicine and British Heart Foundation Centre of Research Excellence, University of Oxford, Level 6, West Wing John Radcliffe Hospital, Headley Way, OX3 9DU, Oxford, UK

    Katja Gehmlich

Authors
  1. Anita Kiran Vimalanathan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elisabeth Ehler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Katja Gehmlich
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Katja Gehmlich.

Ethics declarations

Conflict of interest

Anita Kiran Vimalanathan declares that she has no conflict of interest. Elisabeth Ehler declares that she has no conflict of interest. Katja Gehmlich declares that she has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

This article is part of a Special Issue on ‘Heart Failure Due to Non-Myofibrillar Defects’ edited by Elisabeth Ehler and Katja Gehmlich.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vimalanathan, A.K., Ehler, E. & Gehmlich, K. Genetics of and pathogenic mechanisms in arrhythmogenic right ventricular cardiomyopathy. Biophys Rev 10, 973–982 (2018). https://doi.org/10.1007/s12551-018-0437-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12551-018-0437-0

Keywords

Search

Navigation