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

Background Arrhythmogenic 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 Results Thirty 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. Conclusions Familial 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

PLoS One, 2014, vol. 9, núm. 6, p. e100560

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
Date: 2014
Abstract: Background Arrhythmogenic 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 Results Thirty 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. Conclusions Familial 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
Format: application/pdf
ISSN: 1932-6203
Document access: http://hdl.handle.net/10256/12442
Language: eng
Publisher: Public Library of Science (PLoS)
Collection: Reproducció digital del document publicat a: http://dx.doi.org/10.1371/journal.pone.0100560
Articles publicats (D-CM)
Is part of: PLoS One, 2014, vol. 9, núm. 6, p. e100560
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: DUGiDocs

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