This Article Full Text Full Text (PDF) All Versions of this Article: 113/13/1650    most recent CIRCULATIONAHA.105.609719v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by van Tintelen, J.P. Articles by Hauer, R. N.W. Search for Related Content PubMed PubMed Citation Articles by van Tintelen, J.P. Articles by Hauer, R. N.W. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Protein UniGene Medline Plus Health Information Cardiomyopathy Related Collections Clinical genetics Other diagnostic testing

(Circulation. 2006;113:1650-1658.)
© 2006 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Plakophilin-2 Mutations Are the Major Determinant of Familial Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

J.Peter van Tintelen, MD; Mark M. Entius, PhD; Zahurul A. Bhuiyan, MD, PhD; Roselie Jongbloed, PhD; Ans C.P. Wiesfeld, MD, PhD; Arthur A.M. Wilde, MD, PhD; Jasper van der Smagt, MD; Ludolf G. Boven, BAS; Marcel M.A.M. Mannens, PhD; Irene M. van Langen, MD, PhD; Robert M.W. Hofstra, PhD; Luuk C. Otterspoor, MD; Pieter A.F.M. Doevendans, MD, PhD; Luz-Maria Rodriguez, MD, PhD; Isabelle C. van Gelder, MD, PhD; Richard N.W. Hauer, MD, PhD

From the Department of Clinical Genetics, University Medical Center Groningen, University of Groningen. Groningen (J.P.v.T., L.G.B., R.M.W.H.); Interuniversity Cardiology Institute of the Netherlands, Utrecht (J.P.v.T., A.A.M.W., P.A.F.M.D., R.N.W.H.); Department of Cardiology, Heart Lung Center Utrecht, University Medical Center, Utrecht (M.M.E., L.C.O., P.A.F.M.D., R.N.W.H.); Department of Clinical Genetics, Academic Medical Center, Amsterdam (Z.A.B., M.M.A.M.M., I.M.v.L.); Department of Clinical Genetics, University of Maastricht, Maastricht (R.J.); Department of Cardiology, Thorax Center, University Medical Center Groningen, Groningen (A.C.P.W., I.C.v.G.); Department of Cardiology, Academic Medical Center, Amsterdam (A.A.M.W.); Department of Medical Genetics, University Medical Center Utrecht, Utrecht (J.v.d.S.); and Department of Cardiology, University Hospital Maastricht, Maastricht (L.-M.R.), the Netherlands.

Correspondence to J. Peter van Tintelen, Department of Clinical Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, PO Box 30.001, 9700 RB Groningen, The Netherlands. E-mail p.van.tintelen{at}medgen.umcg.nl

Received December 20, 2005; revision received January 24, 2006; accepted January 27, 2006.

Background— Mutations in the plakophilin-2 gene (PKP2) have been found in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC). Hence, genetic screening can potentially be a valuable tool in the diagnostic workup of patients with ARVC.

Methods and Results— To establish the prevalence and character of PKP2 mutations and to study potential differences in the associated phenotype, we evaluated 96 index patients, including 56 who fulfilled the published task force criteria. In addition, 114 family members from 34 of these 56 ARVC index patients were phenotyped. In 24 of these 56 ARVC patients (43%), 14 different (11 novel) PKP2 mutations were identified. Four different mutations were found more than once; haplotype analyses revealed identical haplotypes in the different mutation carriers, suggesting founder mutations. No specific genotype-phenotype correlations could be identified, except that negative T waves in V₂ and V₃ occurred more often in PKP2 mutation carriers (P<0.05). Of the 34 index patients whose family members were phenotyped, 23 familial cases were identified. PKP2 mutations were identified in 16 of these 23 ARVC index patients (70%) with familial ARVC. On the other hand, no PKP2 mutations at all were found in 11 probands without additional affected family members (P<0.001).

Conclusions— PKP2 mutations can be identified in nearly half of the Dutch patients fulfilling the ARVC criteria. In familial ARVC, even the vast majority (70%) is caused by PKP2 mutations. However, nonfamilial ARVC is not related to PKP2. The high yield of mutational analysis in familial ARVC is unique in inherited cardiomyopathies.

---

 

CLINICAL PERSPECTIVE

This article has been cited by other articles:

				D. Dalal, H. Tandri, D. P. Judge, N. Amat, R. Macedo, R. Jain, C. Tichnell, A. Daly, C. James, S. D. Russell, et al. Morphologic variants of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy a genetics-magnetic resonance imaging correlation study. J. Am. Coll. Cardiol., April 14, 2009; 53(15): 1289 - 1299. [Abstract] [Full Text] [PDF]

				M. Groenink and A. A.M. Wilde The "accordion sign," a new tune in arrhythmogenic right ventricular dysplasia/cardiomyopathy magnetic resonance imaging? J. Am. Coll. Cardiol., April 14, 2009; 53(15): 1300 - 1301. [Full Text] [PDF]

				R. F. Padera Jr. and F. J. Schoen Pathology of Cardiac Surgery Card. Surg. Adult, January 1, 2008; 3(2008): 111 - 178. [Full Text]

				S. Sen-Chowdhry, P. Syrris, and W. J. McKenna Role of Genetic Analysis in the Management of Patients With Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy J. Am. Coll. Cardiol., November 6, 2007; 50(19): 1813 - 1821. [Abstract] [Full Text] [PDF]

				S. Rohr Molecular Crosstalk Between Mechanical and Electrical Junctions at the Intercalated Disc Circ. Res., September 28, 2007; 101(7): 637 - 639. [Full Text] [PDF]

				E. M. Oxford, H. Musa, K. Maass, W. Coombs, S. M. Taffet, and M. Delmar Connexin43 Remodeling Caused by Inhibition of Plakophilin-2 Expression in Cardiac Cells Circ. Res., September 28, 2007; 101(7): 703 - 711. [Abstract] [Full Text] [PDF]

				N. H. Robin, P. B. Tabereaux, R. Benza, and B. R. Korf Genetic Testing in Cardiovascular Disease J. Am. Coll. Cardiol., August 21, 2007; 50(8): 727 - 737. [Abstract] [Full Text] [PDF]

				D. Dalal, R. Jain, H. Tandri, J. Dong, S. M. Eid, K. Prakasa, C. Tichnell, C. James, T. Abraham, S. D. Russell, et al. Long-Term Efficacy of Catheter Ablation of Ventricular Tachycardia in Patients With Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy J. Am. Coll. Cardiol., July 31, 2007; 50(5): 432 - 440. [Abstract] [Full Text] [PDF]

				B. Schroen, J. J. Leenders, A. van Erk, A. T. Bertrand, M. van Loon, R. E. van Leeuwen, N. Kubben, R. F. Duisters, M. W. Schellings, B. J. Janssen, et al. Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophy J. Exp. Med., May 14, 2007; 204(5): 1227 - 1235. [Abstract] [Full Text] [PDF]

				S. Sen-Chowdhry, P. Syrris, D. Ward, A. Asimaki, E. Sevdalis, and W. J. McKenna Clinical and Genetic Characterization of Families With Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Provides Novel Insights Into Patterns of Disease Expression Circulation, April 3, 2007; 115(13): 1710 - 1720. [Abstract] [Full Text] [PDF]

				P. Kirchhof, L. Fabritz, M. Zwiener, H. Witt, M. Schafers, S. Zellerhoff, M. Paul, T. Athai, K.-H. Hiller, H. A. Baba, et al. Age- and Training-Dependent Development of Arrhythmogenic Right Ventricular Cardiomyopathy in Heterozygous Plakoglobin-Deficient Mice Circulation, October 24, 2006; 114(17): 1799 - 1806. [Abstract] [Full Text] [PDF]

				L. Antoniades, A. Tsatsopoulou, A. Anastasakis, P. Syrris, A. Asimaki, D. Panagiotakos, C. Zambartas, C. Stefanadis, W. J. McKenna, and N. Protonotarios Arrhythmogenic right ventricular cardiomyopathy caused by deletions in plakophilin-2 and plakoglobin (Naxos disease) in families from Greece and Cyprus: genotype-phenotype relations, diagnostic features and prognosis Eur. Heart J., September 2, 2006; 27(18): 2208 - 2216. [Abstract] [Full Text] [PDF]

				D. Corrado and G. Thiene Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia: Clinical Impact of Molecular Genetic Studies Circulation, April 4, 2006; 113(13): 1634 - 1637. [Full Text] [PDF]