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Stop-Gain Mutations in PKP2 Are Associated with a Later Age of Onset of Arrhythmogenic Right Ventricular Cardiomyopathy

BackgroundArrhythmogenic right ventricular cardiomyopathy (ARVC) is a cardiac disease characterized by the presence of fibrofatty replacement of the right ventricular myocardium, which may cause ventricular arrhythmias and sudden cardiac death. Pathogenic mutations in several genes encoding mainly desmosomal proteins have been reported. Our aim is to perform genotype-phenotype correlations to establish the diagnostic value of genetics and to assess the role of mutation type in age-related penetrance in ARVC.Methods and ResultsThirty unrelated Spanish patients underwent a complete clinical evaluation. They all were screened for PKP2, DSG2, DSC2, DSP, JUP and TMEM43 genes. A total of 70 relatives of four families were also studied. The 30 patients fulfilled definite disease diagnostic criteria. Genetic analysis revealed a pathogenic mutation in 19 patients (13 in PKP2, 3 in DSG2, 2 in DSP, and 1 in DSC2). Nine of these mutations created a truncated protein due to the generation of a stop codon. Familial assessment revealed 28 genetic carriers among family members. Stop-gain mutations were associated to a later age of onset of ARVC, without differences in the severity of the pathology.ConclusionsFamilial genetic analysis helps to identify the cause responsible for the pathology. In discrepancy with previous studies, the presence of a truncating protein does not confer a worse severity. This information could suggest that truncating proteins may be compensated by the normal allele and that missense mutations may act as poison peptides

Public Library of Science (PLoS)

Author: Alcalde Masegu, Mireia
Campuzano Larrea, Oscar
Berne, Paola
García Pavía, Pablo
Doltra, Ada
Arbelo, Elena
Sarquella Brugada, Georgia
Iglesias, Anna
Alonso Pulpón, Luis
Brugada Terradellas, Josep
Brugada, Ramon
Abstract: BackgroundArrhythmogenic right ventricular cardiomyopathy (ARVC) is a cardiac disease characterized by the presence of fibrofatty replacement of the right ventricular myocardium, which may cause ventricular arrhythmias and sudden cardiac death. Pathogenic mutations in several genes encoding mainly desmosomal proteins have been reported. Our aim is to perform genotype-phenotype correlations to establish the diagnostic value of genetics and to assess the role of mutation type in age-related penetrance in ARVC.Methods and ResultsThirty unrelated Spanish patients underwent a complete clinical evaluation. They all were screened for PKP2, DSG2, DSC2, DSP, JUP and TMEM43 genes. A total of 70 relatives of four families were also studied. The 30 patients fulfilled definite disease diagnostic criteria. Genetic analysis revealed a pathogenic mutation in 19 patients (13 in PKP2, 3 in DSG2, 2 in DSP, and 1 in DSC2). Nine of these mutations created a truncated protein due to the generation of a stop codon. Familial assessment revealed 28 genetic carriers among family members. Stop-gain mutations were associated to a later age of onset of ARVC, without differences in the severity of the pathology.ConclusionsFamilial genetic analysis helps to identify the cause responsible for the pathology. In discrepancy with previous studies, the presence of a truncating protein does not confer a worse severity. This information could suggest that truncating proteins may be compensated by the normal allele and that missense mutations may act as poison peptides
Document access: http://hdl.handle.net/2072/261934
Language: eng
Publisher: Public Library of Science (PLoS)
Rights: Reconeixement 3.0 Espanya
Rights URI: http://creativecommons.org/licenses/by/3.0/es/deed.ca
Subject: Cor -- Malalties
Heart -- Diseases
Arítmia
Arrhythmia
Cor -- Ventricle dret
Heart -- Right ventricle
Fibril·lació ventricular
Ventricular fibrillation
Title: Stop-Gain Mutations in PKP2 Are Associated with a Later Age of Onset of Arrhythmogenic Right Ventricular Cardiomyopathy
Type: info:eu-repo/semantics/article
Repository: Recercat

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