Objectives: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by fibrofatty replacement of cardiomyocytes. In around 50% of index patients, a genetic predisposition is demonstrated. The purpose of this study was to examine a plakophilin-2 (PKP2) splice site mutation, c.2489+4A>C, identified in 4 separately ascertained Dutch ARVD/C families. Methods: Genealogical studies and comprehensive screening of 5 desmosomal genes were undertaken. Reverse transcriptase PCR (RT-PCR) and subsequent sequencing was performed. Results: An A-to-C change (c.2489+4A>C) near the splice donor site of intervening sequence 12 of PKP2 was found in all 4 families. Based on pedigree data and haplotype sharing, a common ancestor should be situated more than 7 generations ago. RT-PCR demonstrated the presence of aberrant messenger RNA. Clinical manifestations ranged from severe disease to nonpenetrance in elderly mutation carriers. Conclusions: This founder mutation in PKP2 is predicted to lead to the presence of a dysfunctional PKP2 protein, whereas most truncating mutations are expected to lead to loss of protein. Mutation carriers displayed a wide range of disease severity, suggesting that PKP2 mutations alone are not sufficient to cause disease, which results in the variable expression and incomplete penetrance characteristic of ARVD/C mutations.

Keywords:
Arrhythmia, Cardiomyopathy, Genetics, Desmosome, Arrhythmogenic right ventricular dysplasia/cardiomyopathy
1.
McKenna WJ, Thiene G, Nava A, Fontaliran F, Blomstrom-Lundqvist C, Fontaine G, Camerini F: Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy – Task Force of the Working Group Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology. Br Heart J 1994;71:215–218.
2.
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. Circulation 2010;121:1533–1541.
3.
Marcus FI, Fontaine GH, Guiraudon G, Frank R, Laurenceau JL, Malergue C, Grosgogeat Y: Right ventricular dysplasia: a report of 24 adult cases. Circulation 1982;65:384–398.
4.
Basso C, Corrado D, Marcus FI, Nava A, Thiene G: Arrhythmogenic right ventricular cardiomyopathy. Lancet 2009;373:1289–1300.
5.
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.
6.
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: Clinical features of arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in plakophilin-2. Circulation 2006;113:1641–1649.
7.
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.
8.
Syrris P, Ward D, Evans A, Asimaki A, Gandjbakhch E, Sen-Chowdhry S, McKenna WJ: Arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in the desmosomal gene desmocollin-2. Am J Hum Genet 2006;79:978–984.
9.
Heuser A, Plovie ER, Ellinor PT, Grossmann KS, Shin JT, Wichter T, Basson CT, Lerman BB, Sasse-Klaassen S, Thierfelder L, MacRae CA, Gerull B: Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet 2006;79:1081–1088.
10.
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: Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy. Circulation 2006;113:1171–1179.
11.
Rampazzo A, Nava A, Malacrida S, Beffagna G, Bauce B, Rossi V, Zimbello R, Simionati B, Basso C, Thiene G, Towbin JA, Danieli GA: Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet 2002;71:1200–1206.
12.
Asimaki A, Syrris P, Wichter T, Matthias P, Saffitz JE, McKenna WJ: A novel dominant mutation in plakoglobin causes arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet 2007;81:964–973.
13.
Tsatsopoulou AA, Protonotarios NI, McKenna WJ: Arrhythmogenic right ventricular dysplasia, a cell adhesion cardiomyopathy: insights into disease pathogenesis from preliminary genotype-phenotype assessment. Heart 2006;92:1720–1723.
14.
van Tintelen JP, Hofstra RM, Wiesfeld AC, van den Berg MP, Hauer RN, Jongbloed JD: Molecular genetics of arrhythmogenic right ventricular cardiomyopathy: emerging horizon? Curr Opin Cardiol 2007;22:185–192.
15.
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: 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 2008;82:809–821.
16.
van Tintelen JP, van Gelder IC, Asimaki A, Suurmeijer AJ, Wiesfeld AC, Jongbloed JD, van den Wijngaard A, Kuks JB, Spaendonck-Zwarts KY, Notermans N, Boven L, van den Heuvel F, Veenstra-Knol HE, Saffitz JE, Hofstra RM, van den Berg MP: Severe cardiac phenotype with right ventricular predominance in a large cohort of patients with a single missense mutation in the DES gene. Heart Rhythm 2009;6:1574–1583.
17.
Klauke B, Kossmann S, Gaertner A, Brand K, Stork I, Brodehl A, Dieding M, Walhorn V, Anselmetti D, Gerdes D, Bohms B, Schulz U, Zu Knyphausen E, Vorgerd M, Gummert J, Milting H: De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy. Hum Mol Genet 2010;19:4595–607.
18.
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: Genetic variation in titin in arrhythmogenic right ventricular cardiomyopathy-overlap syndromes. Circulation 2011;124:876–885.
19.
Xu T, Yang Z, Vatta M, Rampazzo A, Beffagna G, Pillichou K, Scherer S, Saffitz J, Kravitz J, Zareba W, Danieli G, Lorenzon A, Nava A, Bauce B, Thiene G, Basso C, Calkins H, Gear K, Marcus F, Towbin J: Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol 2010;55:587–597.
20.
Fressart V, Duthoit G, Donal E, Probst V, Deharo JC, Chevalier P, Klug D, Dubourg O, Delacretaz E, Cosnay P, Scanu P, Extramiana F, Keller D, Hidden-Lucet F, Simon F, Bessirard V, Roux-Buisson N, Hebert JL, Azarine A, Casset-Senon D, Rouzet F, Lecarpentier Y, Fontaine G, Coirault C, Frank R, Hainque B, Charron P: Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice. Europace 2010;12:861–868.
21.
Cox MG, van der Zwaag PA, van der Werf C, van der Smagt JJ, Noorman M, Bhuiyan ZA, Wiesfeld AC, Volders PG, van Langen IM, Atsma DE, Dooijes D, van den Wijngaard A, Houweling AC, Jongbloed JD, Jordaens L, Cramer MJ, Doevendans PA, de Bakker JM, Wilde AA, van Tintelen JP, Hauer RN: Arrhythmogenic right ventricular dysplasia/cardiomyopathy: pathogenic desmosome mutations in index-patients predict outcome of family screening – Dutch Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Genotype-Phenotype Follow-Up Study. Circulation 2011;123:2690–2700.
22.
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.
23.
Basso C, Czarnowska E, Della Barbera M, Bauce B, Beffagna G, Wlodarska EK, Pilichou K, Ramondo A, Lorenzon A, Wozniek O, Corrado D, Daliento L, Danieli GA, Valente M, Nava A, Thiene G, Rampazzo A: Ultrastructural evidence of intercalated disc remodelling in arrhythmogenic right ventricular cardiomyopathy: an electron microscopy investigation on endomyocardial biopsies. Eur Heart J 2006;27:1847–1854.
24.
Garcia-Gras E, Lombardi R, Giocondo MJ, Willerson JT, Schneider MD, Khoury DS, Marian AJ: Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy. J Clin Invest 2006;116:2012–2021.
25.
Asimaki A, Tandri H, Huang H, Halushka MK, Gautam S, Basso C, Thiene G, Tsatsopoulou A, Protonotarios N, McKenna WJ, Calkins H, Saffitz JE: A new diagnostic test for arrhythmogenic right ventricular cardiomyopathy. N Engl J Med 2009;360:1075–1084.
26.
Syrris P, Ward D, Asimaki A, Sen-Chowdhry S, Ebrahim HY, Evans A, Hitomi N, Norman M, Pantazis A, Shaw AL, Elliott PM, McKenna WJ: Clinical expression of plakophilin-2 mutations in familial arrhythmogenic right ventricular cardiomyopathy. Circulation 2006;113:356–364.
27.
den Haan AD, Tan B, Zikusoka M, Ibanez Llado L, Jain R, Daly A, Tichnell C, James C, Amat-Alarcon N, Abraham T, Russell S, Bluemke D, Calkins H, Dalal D, Judge D: Comprehensive desmosome mutation analysis in North Americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Cardiovasc Genet 2009;2:428–435.
28.
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.
29.
Christensen AH, Benn M, Tybjaerg-Hansen A, Haunso S, Svendsen JH: Missense variants in plakophilin-2 in arrhythmogenic right ventricular cardiomyopathy patients – disease-causing or innocent bystanders? Cardiology 2010;115:148–154.
30.
Lykke-Andersen J: mRNA quality control: marking the message for life or death. Curr Biol 2001;11:R88–R91.
31.
Houwen RH, Baharloo S, Blankenship K, Raeymaekers P, Juyn J, Sandkuijl LA, Freimer NB: Genome screening by searching for shared segments: mapping a gene for benign recurrent intrahepatic cholestasis. Nat Genet 1994;8:380–386.
32.
Bhuiyan ZA, Jongbloed JD, van der Smagt J, Lombardi PM, Wiesfeld AC, Nelen M, Schouten M, Jongbloed R, Cox MG, van Wolferen M, Rodriguez LM, van Gelder IC, Bikker H, Suurmeijer AJ, van den Berg MP, Mannens MM, Hauer RN, Wilde AA, van Tintelen JP: Desmoglein-2 and desmocollin-2 mutations in Dutch arrhythmogenic right ventricular dysplasia/cardiomyopathy patients: results from a multicenter study. Circ Cardiovasc Genet 2009;2:418–427.
33.
van der Zwaag PA, van Tintelen JP, Gerbens F, Jongbloed JD, Boven LG, van der Smagt JJ, van der Roest WP, van Langen IM, Bikker H, Hauer RN, van den Berg MP, Hofstra RM, te Meerman GJ: Haplotype sharing test maps genes for familial cardiomyopathies. Clin Genet 2011;79:459–467.
34.
van der Zwaag PA, Cox MG, van der Werf C, Wiesfeld AC, Jongbloed JD, Dooijes D, Bikker H, Jongbloed R, Suurmeijer AJ, van den Berg MP, Hofstra RM, Hauer RN, Wilde AA, van Tintelen JP: Recurrent and founder mutations in The Netherlands: plakophilin-2 pArg79X mutation causing arrhythmogenic right ventricular cardiomyopathy/dysplasia. Neth Heart J 2010;18:583–591.
35.
Chen X, Bonne S, Hatzfeld M, van Roy F, Green KJ: Protein binding and functional characterization of plakophilin 2: evidence for its diverse roles in desmosomes and beta-catenin signaling. J Biol Chem 2002;277:10512–10522.
36.
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.
© 2012 S. Karger AG, Basel
2012
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.