A novel variant in plakophilin-2 gene detected in a family with arrhythmogenic right ventricular cardiomyopathy

  • Bozena Ostrowska DahlgrenEmail author
  • Marie Allen
  • Anne-Cristine Lindström
  • Mia Bjerke
  • Carina Blomström-Lundqvist



Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by fibrofatty replacement of muscular fibers predominantly in the right ventricle and with ventricular arrhythmias as the main clinical manifestation. Mutations in several components of the desmosome genes have been identified and mutations of the plakophilin-2 (PKP-2) gene are a common cause of ARVC. The aim of this study is to investigate the correlation between genotype and phenotype in a family with a novel PKP-2 variant.

Methods and results

This study describes the clinical findings and genetic analysis in a family with ARVC. A part of the family has been followed clinically long term for up to 27 years. Two not previously reported PKP-2 variants (L506P and T526A) have been identified in this family. Even though all members of this family share the novel variant L506P, the clinical features, i.e., their phenotypes are different. The L506P variant is located in exon 7 and affects a highly conserved residue. The same amino acid, leucine, is present in all species evaluated, indicating a functional importance and the variant is predicted to be damaging. The novel L506P variant in the PKP-2 gene is thus a possible pathogenic alteration in the described family with ARVC. In contrast, the T526A variant is weakly conserved and predicted to be tolerated.


While many of the reported ARVC mutations are truncating mutations, the possibly damaging variant found in this family, is a missense alteration affecting a highly conserved residue 506 located in exon 7.


Arrhythmogenic right ventricular cardiomyopathy Cardiomyopathy Gene mutation Plakophilin-2 gene Desmosome 



We would like to thank J.P. Van Tintelen and J.D.H. Jongbloed, Department of Genetics University Medical Center Groningen, the Netherlands, for kindly providing the primers sequences to exon 1 and 12, as well as control samples. The study was supported by the Swedish Heart-Lung Foundation.

Conflict of interest

None declared.


  1. 1.
    Corrado, D., Basso, C., & Thiene, G. (2009). Arrhythmogenic right ventricular cardiomyopathy: an update. Heart, 95, 766–773.PubMedCrossRefGoogle Scholar
  2. 2.
    Herren, T., Gerber, P. A., & Duru, F. (2009). Arrhythmogenic right ventricular cardiomyopathy/dysplasia: a not so rare "disease of the desmosome" with multiple clinical presentations. Clinical Research in Cardiology, 98, 141–158.PubMedCrossRefGoogle Scholar
  3. 3.
    Hauer, R. N. (2009). Toward early diagnosis in arrhythmogenic right ventricular dysplasia/cardiomyopathy. Journal of Interventional Cardiac Electrophysiology, 26, 1–2.PubMedCrossRefGoogle Scholar
  4. 4.
    Basso, C., Corrado, D., Marcus, F. I., Nava, A., & Thiene, G. (2009). Arrhythmogenic right ventricular cardiomyopathy. Lancet, 373, 1289–1300.PubMedCrossRefGoogle Scholar
  5. 5.
    Sen-Chowdhry, S., Syrris, P., & McKenna, W. J. (2007). Role of genetic analysis in the management of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy. Journal of the American College of Cardiology, 50, 1813–1821.PubMedCrossRefGoogle Scholar
  6. 6.
    B-Lundqvist, C., Eneström, S., Edvardsson, N., & Olsson, S. B. (1987). Arrhythmogenic right ventricular dysplasia presenting with ventricular tachycardia in a father and son. Clinical Cardiology, 10, 277–283.PubMedCrossRefGoogle Scholar
  7. 7.
    Corrado, D., Buja, G., Basso, C., & Thiene, G. (2000). Clinical diagnosis and management strategies in arrhythmogenic right ventricular cardiomyopathy. Journal of Electrocardiology, 33, 49–55.PubMedCrossRefGoogle Scholar
  8. 8.
    Chair, F., McKenna, W., Sherrill, D., Basso, C., et al. (2010). Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy proposed modification of the Task Force Criteria. European Heart Journal, 31, 806–814.CrossRefGoogle Scholar
  9. 9.
    den Haan, A. D., Tan, B. Y., Zikusoka, M. N., Llado, L. I., Jain, R., Daly, A., et al. (2009). Comprehensive desmosome mutation analysis in North Americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circulation Cardiovascular Genetics, 2(5), 428–435.CrossRefGoogle Scholar
  10. 10.
    Kapplinger, J. D., Landstrom, A. P., Salisbury, B. A., Callis, T. E., Pollevick, G. D., Tester, D. J., Cox, M. G., Bhuiyan, Z., Bikker, H., Wiesfeld, A. C., Hauer, R. N., van Tintelen, J. P., Jongbloed, J. D., Calkins, H., Judge, D. P., Wilde, A. A., & Ackerman, M. J. (2011). Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia-associated mutations from background genetic noise. Journal of the American College of Cardiology, 57(23), 2317–2327.PubMedCrossRefGoogle Scholar
  11. 11.
    Lahtinen, M., et al. (2008). Plakophilin-2 missense mutations in arrhythmogenic right ventricular cardiomyopathy. International Journal of Cardiology, 126, 92–100.PubMedCrossRefGoogle Scholar
  12. 12.
    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(9):Google Scholar
  13. 13.
    Bauce, B., Basso, C., & Nava, A. (2002). Signal-averaged electrocardiographic parameter progression as a marker of increased electrical instability in two cases with an overt form of arrhythmogenic right ventricular cardiomyopathy. Journal of Pacing and Clinical Electrophysiology, 25, 362–364.CrossRefGoogle Scholar
  14. 14.
    Turrini, P., Angelini, A., Thiene, G., Buja, G., Daliento, L., Rizzoli, G., & Nava, A. (1999). Late potentials and ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy. The American Journal of Cardiology, 83, 1214–1219.PubMedCrossRefGoogle Scholar
  15. 15.
    van Tintelen, J., Hofstra, R., Wiesfeld, A., van den Berg, M., Hauer, R., & Jongbloed, J. D. (2007). Molecular genetics of arrhythmogenic right ventricular cardiomyopathy: Emerging horizon? Current Opinion in Cardiology, 22, 185–192.PubMedCrossRefGoogle Scholar
  16. 16.
    Calabrese, F., Basso, C., Carturan, E., Valente, M., & Thiene, G. (2006). Arrhythmogenic right ventricular cardiomyopathy/dysplasia: Is there a role for viruses? Cardiovascular Pathology, 15, 11–17.PubMedCrossRefGoogle Scholar
  17. 17.
    Lindstrom, L., Nylander, E., Larsson, H., & Wranne, B. (2005). Left ventricular involvement in arrhytmogenic right ventricular cardiomyopathy—A scintigraphic and echocardiographic study. Clinical Physiology and Functional Imaging, 25, 171–177.PubMedCrossRefGoogle Scholar
  18. 18.
    Moric-Janiszewska, E., & Markiewicz-Loskot, G. (2007). Review of the genetics of arrhytmogenic right ventricular dysplasia. Europace, 9, 259–266.PubMedCrossRefGoogle Scholar
  19. 19.
    Sen-Chowdhry, S., Syrris, P., Prasad, S., Hughes, S., Merrifield, R., Ward, D., Pennell, D., & McKenna, W. (2008). Left-dominant arrhythmogenic cardiomyopathy. Journal of the American College of Cardiology, 25, 2175–2187.CrossRefGoogle Scholar
  20. 20.
    Sen-Chowdhry, S., Syrris, P., Ward, D., Asimaki, A., Sevdalis, E., & Mckenna, W. (2007). Clinical and genetic characterization of families with arrhythmogenic right ventricular dysplasia/cardiomyopathy provides novel insights into pattern of disease expression. Circulation, 115, 1710–1720.PubMedCrossRefGoogle Scholar
  21. 21.
    Sen-Chowdhry, S., Syrris, P., & McKenna, W. (2005). Desmoplakin disease in arrhythmogenic right ventricular cardiomyopathy: Early genotype-phenotype studies. European Heart Journal, 26, 1582–1584.PubMedCrossRefGoogle Scholar
  22. 22.
    Christensen, A. H., Benn, M., Tybjaerg-Hansen, A., Haunso, S., & Svendsen, J. H. (2010). Missense variants in plakophilin-2 in arrhythmogenic right ventricular cardiomyopathy patients–disease-causing or innocent bystanders? Cardiology, 115(2), 148–154.PubMedCrossRefGoogle Scholar
  23. 23.
    Tomas, M., Napolitano, C., De Giuli, L., Bloise, R., et al. (2010). Polymorphism in the NOS1AP gene modulate QT interval duration and risk of arrhythmias in the long QT syndrome. Journal of the American College of Cardiology, 55, 2746–2752.CrossRefGoogle Scholar
  24. 24.
    Barahona-Dussault, C., Benito, B., Campuzano, O., Iglesias, A., Leung, T. L., Robb, L., Talajic, M., & Brugada, R. (2010). Role of genetic testing in arrhythmogenic right ventricular cardiomyopathy/dysplasia. Clinical Genetics, 77(1), 37–48. Epub 2009 Oct 15.PubMedCrossRefGoogle Scholar
  25. 25.
    van Rijen, H. V., Eckardt, D., Degen, J., Theis, M., Ott, T., Willecke, K., Jongsma, H. J., Opthof, T., & de Bakker, J. M. (2004). Slow conduction and enhanced anisotropy increase the propensity for ventricular tachyarrhythmias in adult mice with induced deletion of connexin43. Circulation, 109, 1048–1055.PubMedCrossRefGoogle Scholar
  26. 26.
    Sato, P. Y., Musa, H., Coombs, W., Guerrero-Serna, G., Patino, G. A., Taffet, S. M., Isom, L. L., & Delmar, M. (2009). Loss of plakophilin-2 expression leads to decreased sodium current and slower conduction velocity in cultured cardiac myocytes. Circulation Research, 105, 523–526.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Bozena Ostrowska Dahlgren
    • 1
    Email author
  • Marie Allen
    • 2
  • Anne-Cristine Lindström
    • 2
  • Mia Bjerke
    • 2
  • Carina Blomström-Lundqvist
    • 1
  1. 1.Department of CardiologyUppsala UniversityUppsalaSweden
  2. 2.Department of Immunology, Genetics and PathologyUppsala UniversityUppsalaSweden

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