Clinical and Genetic Characterization of Patients with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Caused by a Plakophilin-2 Splice Mutationvan der Smagt J.J. · van der Zwaag P.A. · van Tintelen J.P. · Cox M.G.P.J. · Wilde A.A.M. · van Langen I.M. · Ummels A. · Hennekam F.A.M. · Dooijes D. · Gerbens F. · Bikker H. · Hauer R.N.W. · Doevendans P.A.
Departments of aMedical Genetics and bCardiology, University Medical Center Utrecht, University of Utrecht, and cInteruniversity Cardiology Institute of The Netherlands, Utrecht, dDepartment of Genetics, University of Groningen, University Medical Center Groningen, Groningen, and eHeart Failure Research Center and fDepartment of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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.
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