title: Clinical expression of plakophilin-2 mutations in familial arrhythmogenic right ventricular cardiomyopathy.
abstract: BACKGROUND
  Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disorder characterized by loss of cardiomyocytes and their replacement by adipose and fibrous tissue. It is considered a disease of cell adhesion because mutations in desmosomal genes, desmoplakin and plakoglobin, have been implicated in the pathogenesis of ARVC. In a recent report, mutations in plakophilin-2, a gene highly expressed in cardiac desmosomes, have been shown to cause ARVC.
  
  
  RESULTS
  We investigated 100 white patients with ARVC for mutations in plakophilin-2. Nine different mutations were identified by direct sequencing in 11 cases. Five of these mutations are novel (A733fsX740, L586fsX658, V570fsX576, R413X, and P533fsX561) and predicted to cause a premature truncation of the plakophilin-2 protein. Family studies showed incomplete disease expression in mutation carriers and identified a number of individuals who would be misdiagnosed with the existing International Task Force and modified diagnostic criteria for ARVC.
  
  
  CONCLUSIONS
  In this study, we provide new evidence that mutations in the desmosomal plakophilin-2 gene can cause ARVC. A systematic clinical evaluation of mutation carriers within families demonstrated variable phenotypic expression, even among individuals with the same mutation, and highlighted the need for a more accurate set of diagnostic criteria for ARVC.
authors.affiliation: Department of Medicine, University College London Hospitals Trust, London, UK.
authors.forename: Petros
authors.initials: P
authors.lastname: Syrris
authors.forename: Deirdre
authors.initials: D
authors.lastname: Ward
authors.forename: Angeliki
authors.initials: A
authors.lastname: Asimaki
authors.forename: Srijita
authors.initials: S
authors.lastname: Sen-Chowdhry
authors.forename: Hatim Y
authors.initials: HY
authors.lastname: Ebrahim
authors.forename: Alison
authors.initials: A
authors.lastname: Evans
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Hitomi
authors.forename: Mark
authors.initials: M
authors.lastname: Norman
authors.forename: Antonios
authors.initials: A
authors.lastname: Pantazis
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Shaw
authors.forename: Perry M
authors.initials: PM
authors.lastname: Elliott
authors.forename: William J
authors.initials: WJ
authors.lastname: McKenna
mesh_terms: D000293:Adolescent; D000328:Adult; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics* / Q000473:pathology; D002648:Child; D018389:Codon, Nonsense; D016757:Death, Sudden, Cardiac; D003896:Desmosomes / Q000473:pathology; D005192:Family Health; D005260:Female; D016368:Frameshift Mutation; D017353:Gene Deletion; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D051191:Plakophilins / Q000235:genetics*; D022821:RNA Splice Sites
chemical_list: D018389:Codon, Nonsense; C495337:PKP2 protein, human; D051191:Plakophilins; D022821:RNA Splice Sites