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- Title
Clinical and Genetic Characterization of Patients with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Caused by a Plakophilin-2 Splice Mutation.
- Authors
van der Smagt, Jasper J.; van der Zwaag, Paul A.; van Tintelen, J. Peter; Cox, Moniek G.P.J.; Wilde, Arthur A.M.; van Langen, Irene M.; Ummels, Amber; Hennekam, F.A.M.; Dooijes, Dennis; Gerbens, Frans; Bikker, Hennie; Hauer, Richard N.W.; Doevendans, Pieter A.
- Abstract
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. Copyright © 2012 S. Karger AG, Basel
- Subjects
CARDIOMYOPATHIES; ATRIAL fibrillation risk factors; MOVEMENT disorders; MESSENGER RNA; HEART cells
- Publication
Cardiology, 2012, Vol 123, Issue 3, p181
- ISSN
0008-6312
- Publication type
Article
- DOI
10.1159/000342717