title: Novel missense mutations in exon 15 of desmoglein-2: role of the intracellular cadherin segment in arrhythmogenic right ventricular cardiomyopathy?
abstract: BACKGROUND
  The diagnosis of arrhythmogenic right ventricular cardiomyopathy can be challenging. Disease-causing mutations in desmosomal genes have been identified. A novel diagnostic feature, loss of immunoreactivity for plakoglobin from the intercalated disks, recently was proposed.
  
  
  OBJECTIVE
  The purpose of this study was to identify two novel mutations in the intracellular cadherin segment of desmoglein-2 (G812S and C813R in exon 15). Co-segregation of the G812S mutation with disease expression was established in a large Caucasian family. Endomyocardial biopsies of two individuals showed reduced plakoglobin signal at the intercalated disk.
  
  
  METHODS
  To understand the pathologic changes occurring in the diseased myocardium, functional studies on three mutations in exon 15 of desmoglein-2 (G812C, G812S, C813R) were performed.
  
  
  RESULTS
  Localization studies failed to detect any differences in targeting or stability of the mutant proteins, suggesting that they act via a dominant negative mechanism. Binding assays were performed to probe for altered binding affinities toward other desmosomal proteins, such as plakoglobin and plakophilin-2. Although no differences were observed for the mutated proteins in comparison to wild-type desmoglein-2, binding to plakophilin-2 depended on the expression system (i.e., bacterial vs mammalian protein expression). In addition, abnormal migration of the C813R mutant protein was observed in gel electrophoresis.
  
  
  CONCLUSIONS
  Loss of plakoglobin immunoreactivity from the intercalated disks appears to be the endpoint of complex pathologic changes, and our functional data suggest that yet unknown posttranslational modifications of desmoglein-2 might be involved.
authors: Institute of Cardiovascular Science, University College London, United Kingdom. katja.gehmlich@cardiov.ox.ac.uk
authors: Katja
authors: K
authors: Gehmlich
authors: Angeliki
authors: A
authors: Asimaki
authors: Thomas J
authors: TJ
authors: Cahill
authors: Elisabeth
authors: E
authors: Ehler
authors: Petros
authors: P
authors: Syrris
authors: Elisabetta
authors: E
authors: Zachara
authors: Federica
authors: F
authors: Re
authors: Andrea
authors: A
authors: Avella
authors: Lorenzo
authors: L
authors: Monserrat
authors: Jeffrey E
authors: JE
authors: Saffitz
authors: William J
authors: WJ
authors: McKenna
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D001707:Biopsy, Needle; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D051301:Desmoglein 2 / Q000235:genetics* / Q000378:metabolism; D004699:Endocardium / Q000378:metabolism / Q000473:pathology; D005260:Female; D005838:Genotype; D006352:Heart Ventricles / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D051191:Plakophilins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D055815:Young Adult; D051185:gamma Catenin / Q000276:immunology / Q000378:metabolism
chemical_list: D015820:Cadherins; D051301:Desmoglein 2; D051191:Plakophilins; D051185:gamma Catenin