title: Characterization of the molecular phenotype of two arrhythmogenic right ventricular cardiomyopathy (ARVC)-related plakophilin-2 (PKP2) mutations.
abstract: BACKGROUND
  Arrhythmogenic right ventricular cardiomyopathy (ARVC) has been linked to mutations in desmosomal proteins, including plakophilin-2 (PKP2). Little is known about the changes in cellular function and structure that follow expression of ARVC-relevant PKP2 mutations.
  
  
  OBJECTIVE
  The purpose of this study was to investigate the function and distribution of an ARVC-relevant PKP2 mutant where arginine at position 79 was replaced by a stop codon (R79x).
  
  
  METHODS
  Results were compared with those obtained with mutation 179fs (frameshift at position 179). Mutant constructs were introduced by adenoviral infection into neonatal rat ventricular myocytes in culture.
  
  
  RESULTS
  Both mutant proteins failed to preferentially localize to sites of cell-cell apposition. Their expression did not disrupt localization of endogenous PKP2, connexin-43 (Cx43), or desmoplakin (DP). However, we observed reduced abundance of Cx43 after R79x expression. Early truncation of PKP2 at position 79 also prevented its physical interaction with both DP and Cx43. Finally, R79x expression correlated with loss of expression of HSP90, a protein relevant to cardiomyocyte apoptosis.
  
  
  CONCLUSIONS
  These results provide the first observations of the cellular/molecular phenotype consequent to these PKP2 mutations and give insight into the possible cellular substrates that lead to ARVC.
authors.affiliation: Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York, USA.
authors.forename: Rosy
authors.initials: R
authors.lastname: Joshi-Mukherjee
authors.forename: Wanda
authors.initials: W
authors.lastname: Coombs
authors.forename: Hassan
authors.initials: H
authors.lastname: Musa
authors.forename: Eva
authors.initials: E
authors.lastname: Oxford
authors.forename: Steven
authors.initials: S
authors.lastname: Taffet
authors.forename: Mario
authors.initials: M
authors.lastname: Delmar
mesh_terms: D017209:Apoptosis; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D051191:Plakophilins / Q000235:genetics* / Q000378:metabolism
chemical_list: D018031:Connexin 43; C495337:PKP2 protein, human; D051191:Plakophilins; D004247:DNA