title: Stop-gain mutations in PKP2 are associated with a later age of onset of arrhythmogenic right ventricular cardiomyopathy.
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.
  
  
  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.
authors: Cardiovascular Genetics Centre, University of Girona-IDIBGI, Girona, Spain.
authors: Mireia
authors: M
authors: Alcalde
authors: Cardiovascular Genetics Centre, University of Girona-IDIBGI, Girona, Spain.
authors: Oscar
authors: O
authors: Campuzano
authors: Arrhythmia Section, Thorax Institute, Hospital Clinic, Barcelona, Spain.
authors: Paola
authors: P
authors: Berne
authors: Cardiomyopathy Unit, Heart Failure and Heart Transplant Section, Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain.
authors: Pablo
authors: P
authors: García-Pavía
authors: Arrhythmia Section, Thorax Institute, Hospital Clinic, Barcelona, Spain.
authors: Ada
authors: A
authors: Doltra
authors: Arrhythmia Section, Thorax Institute, Hospital Clinic, Barcelona, Spain.
authors: Elena
authors: E
authors: Arbelo
authors: Arrhythmia Section, Hospital Sant Joan de Deu, Barcelona, Spain.
authors: Georgia
authors: G
authors: Sarquella-Brugada
authors: Cardiovascular Genetics Centre, University of Girona-IDIBGI, Girona, Spain.
authors: Anna
authors: A
authors: Iglesias
authors: Cardiomyopathy Unit, Heart Failure and Heart Transplant Section, Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain.
authors: Luis
authors: L
authors: Alonso-Pulpon
authors: Arrhythmia Section, Thorax Institute, Hospital Clinic, Barcelona, Spain.
authors: Josep
authors: J
authors: Brugada
authors: Cardiovascular Genetics Centre, University of Girona-IDIBGI, Girona, Spain.
authors: Ramon
authors: R
authors: Brugada
mesh_terms: D000328:Adult; D017668:Age of Onset; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000453:epidemiology* / Q000235:genetics*; D002648:Child; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051191:Plakophilins / Q000235:genetics*; D015995:Prevalence; D013030:Spain / Q000453:epidemiology; D055815:Young Adult
chemical_list: C495337:PKP2 protein, human; D051191:Plakophilins