Stop-gain mutations in PKP2 are associated with a later age of onset of arrhythmogenic right ventricular cardiomyopathy.

<h4>Background</h4>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 ge...

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Autores principales:	Mireia Alcalde, Oscar Campuzano, Paola Berne, Pablo García-Pavía, Ada Doltra, Elena Arbelo, Georgia Sarquella-Brugada, Anna Iglesias, Luis Alonso-Pulpon, Josep Brugada, Ramon Brugada
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/056fba4deb9c4634a5510ddfb55b9c74
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spelling	oai:doaj.org-article:056fba4deb9c4634a5510ddfb55b9c742021-11-11T08:21:29ZStop-gain mutations in PKP2 are associated with a later age of onset of arrhythmogenic right ventricular cardiomyopathy.1932-620310.1371/journal.pone.0100560https://doaj.org/article/056fba4deb9c4634a5510ddfb55b9c742014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24967631/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methods and results</h4>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.<h4>Conclusions</h4>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.Mireia AlcaldeOscar CampuzanoPaola BernePablo García-PavíaAda DoltraElena ArbeloGeorgia Sarquella-BrugadaAnna IglesiasLuis Alonso-PulponJosep BrugadaRamon BrugadaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 6, p e100560 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mireia Alcalde Oscar Campuzano Paola Berne Pablo García-Pavía Ada Doltra Elena Arbelo Georgia Sarquella-Brugada Anna Iglesias Luis Alonso-Pulpon Josep Brugada Ramon Brugada Stop-gain mutations in PKP2 are associated with a later age of onset of arrhythmogenic right ventricular cardiomyopathy.
description	<h4>Background</h4>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.<h4>Methods and results</h4>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.<h4>Conclusions</h4>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	article
author	Mireia Alcalde Oscar Campuzano Paola Berne Pablo García-Pavía Ada Doltra Elena Arbelo Georgia Sarquella-Brugada Anna Iglesias Luis Alonso-Pulpon Josep Brugada Ramon Brugada
author_facet	Mireia Alcalde Oscar Campuzano Paola Berne Pablo García-Pavía Ada Doltra Elena Arbelo Georgia Sarquella-Brugada Anna Iglesias Luis Alonso-Pulpon Josep Brugada Ramon Brugada
author_sort	Mireia Alcalde
title	Stop-gain mutations in PKP2 are associated with a later age of onset of arrhythmogenic right ventricular cardiomyopathy.
title_short	Stop-gain mutations in PKP2 are associated with a later age of onset of arrhythmogenic right ventricular cardiomyopathy.
title_full	Stop-gain mutations in PKP2 are associated with a later age of onset of arrhythmogenic right ventricular cardiomyopathy.
title_fullStr	Stop-gain mutations in PKP2 are associated with a later age of onset of arrhythmogenic right ventricular cardiomyopathy.
title_full_unstemmed	Stop-gain mutations in PKP2 are associated with a later age of onset of arrhythmogenic right ventricular cardiomyopathy.
title_sort	stop-gain mutations in pkp2 are associated with a later age of onset of arrhythmogenic right ventricular cardiomyopathy.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/056fba4deb9c4634a5510ddfb55b9c74
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Stop-gain mutations in PKP2 are associated with a later age of onset of arrhythmogenic right ventricular cardiomyopathy.

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