Swipe om te navigeren naar een ander artikel
Background. Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited cardiac disease with reduced penetrance and a highly variable expression. Mutations in the gene encoding the plakophilin-2 gene (PKP2) are detected in about 50% of ARVC/D patients. The p.Arg79X mutation in PKP2 has been identified in Europe and North America and has been functionally characterised. We evaluated the prevalence of the p.Arg79X mutation in PKP2 in the Dutch population.
Methods. Twelve index patients and 41 family members were evaluated in three university hospitals in the Netherlands. The diagnosis of ARVC/D was established according to the recently revised Task Force Criteria. Segregation of the p.Arg79X mutation was studied and haplotypes were reconstructed to determine whether the p.Arg79X mutation was a recurrent or a founder mutation.
Results. The p.Arg79X mutation in PKP2 was identified in 12 index patients. Haplotype analysis revealed a shared haplotype among Dutch p.Arg79X mutation carriers, indicating a common founder. Six index patients (50%) had a first- or second-degree relative who had died of sudden cardiac death below 40 years of age. At age 60, only 60% of the mutation carriers had experienced any symptoms. There was no significant difference in symptom-free survival and event-free survival between men and women.
Conclusion. We have identified the largest series of patients with the same desmosome gene mutation in ARVC/D reported to date. This p.Arg79X mutation in PKP2 is a founder mutation in the Dutch population. The phenotypes of PKP2 p.Arg79X mutation carriers illustrate the clinical variability and reduced penetrance often seen in ARVC/D. (Neth Heart J 2010;18:583–91.)
Log in om toegang te krijgen
Met onderstaand(e) abonnement(en) heeft u direct toegang:
Marcus FI, Fontaine GH, Guiraudon G, Frank R, Laurenceau JL, Malergue C, et al. Right ventricular dysplasia: a report of 24 adult cases. Circulation. 1982;65:384–398. PubMed
McKenna WJ, Thiene G, Nava A, Fontaliran F, Blomstrom-Lundqvist C, Fontaine G, et al. 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. PubMedCrossRef
den Haan AD, Tan B, Zikusoka M, Ibanez Llado L, Jain R, Daly A, et al. Comprehensive Desmosome Mutation Analysis in North Americans with Arrhythmogenic Right Ventricular Dysplasia/ Cardiomyopathy. Circ Cardiovasc Genet. 2009;2:428–435. CrossRef
van der Zwaag PA, Jongbloed JD, van den Berg MP, van der Smagt JJ, Jongbloed R, Bikker H, et al. A genetic variants database for arrhythmogenic right ventricular dysplasia/cardiomyopathy. Hum Mutat. 2009;30:1278–83; available from http://www.arvcdatabase.info.
Rodriguez-Sinovas A, Boengler K, Cabestrero A, Gres P, Morente M, Ruiz-Meana M, et al. Translocation of connexin 43 to the inner mitochondrial membrane of cardiomyocytes through the heat shock protein 90-dependent TOM pathway and its importance for cardioprotection. Circ Res. 2006;99:93–101. PubMedCrossRef
Recurrent and founder mutations in the Netherlands
Plakophilin-2 p.Arg79X mutation causing arrhythmogenic right ventricular cardiomyopathy/dysplasia
P.A. van der Zwaag
C. van der Werf
M.P. van den Berg
J.P. van Tintelen
- Bohn Stafleu van Loghum