title: Clinical and genetic characterization of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy caused by a plakophilin-2 splice mutation.
abstract: OBJECTIVE
  Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by fibrofatty replacement of cardiomyocytes. In around 50% of index patients, a genetic predisposition is demonstrated. The purpose of this study was to examine a plakophilin-2 (PKP2) splice site mutation, c.2489+4A>C, identified in 4 separately ascertained Dutch ARVD/C families.
  
  
  METHODS
  Genealogical studies and comprehensive screening of 5 desmosomal genes were undertaken. Reverse transcriptase PCR (RT-PCR) and subsequent sequencing was performed.
  
  
  RESULTS
  An A-to-C change (c.2489+4A>C) near the splice donor site of intervening sequence 12 of PKP2 was found in all 4 families. Based on pedigree data and haplotype sharing, a common ancestor should be situated more than 7 generations ago. RT-PCR demonstrated the presence of aberrant messenger RNA. Clinical manifestations ranged from severe disease to nonpenetrance in elderly mutation carriers.
  
  
  CONCLUSIONS
  This founder mutation in PKP2 is predicted to lead to the presence of a dysfunctional PKP2 protein, whereas most truncating mutations are expected to lead to loss of protein. Mutation carriers displayed a wide range of disease severity, suggesting that PKP2 mutations alone are not sufficient to cause disease, which results in the variable expression and incomplete penetrance characteristic of ARVD/C mutations.
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, University of Utrecht, The Netherlands. j.j.vandersmagt@umcutrecht.nl
authors.forename: Jasper J
authors.initials: JJ
authors.lastname: van der Smagt
authors.forename: Paul A
authors.initials: PA
authors.lastname: van der Zwaag
authors.forename: J Peter
authors.initials: JP
authors.lastname: van Tintelen
authors.forename: Moniek G P J
authors.initials: MG
authors.lastname: Cox
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.forename: Irene M
authors.initials: IM
authors.lastname: van Langen
authors.forename: Amber
authors.initials: A
authors.lastname: Ummels
authors.forename: F A M
authors.initials: FA
authors.lastname: Hennekam
authors.forename: Dennis
authors.initials: D
authors.lastname: Dooijes
authors.forename: Frans
authors.initials: F
authors.lastname: Gerbens
authors.forename: Hennie
authors.initials: H
authors.lastname: Bikker
authors.forename: Richard N W
authors.initials: RN
authors.lastname: Hauer
authors.forename: Pieter A
authors.initials: PA
authors.lastname: Doevendans
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D051191:Plakophilins / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics; D055815:Young Adult
chemical_list: D051191:Plakophilins; D022821:RNA Splice Sites