title: Remodeling of myocyte gap junctions in arrhythmogenic right ventricular cardiomyopathy due to a deletion in plakoglobin (Naxos disease).
abstract: OBJECTIVE
  We tested the hypothesis that defective interactions between adhesion junctions and the cytoskeleton caused by the plakoglobin mutation in Naxos disease lead to remodeling of gap junctions and altered expression of the major gap junction protein, connexin43.
  
  
  BACKGROUND
  Naxos disease, a recessive form of arrhythmogenic right ventricular cardiomyopathy, is associated with a high incidence of arrhythmias and sudden cardiac death. Naxos disease is caused by a mutation in plakoglobin, a protein that links cell-cell adhesion molecules to the cytoskeleton.
  
  
  METHODS
  Myocardial expression of connexin43 and other intercellular junction proteins was characterized in 4 patients with Naxos disease. Immunohistochemistry was performed in all 4 patients, and immunoblotting and electron microscopy were performed in 1 patient who died in childhood before overt arrhythmogenic right ventricular cardiomyopathy had developed.
  
  
  RESULTS
  Connexin43 expression at intercellular junctions was reduced significantly in both right and left ventricles in all patients with Naxos disease. Electron microscopy revealed smaller and fewer gap junctions interconnecting ventricular myocytes. Mutant plakoglobin was expressed but failed to localize normally at intercellular junctions. Localization of N-cadherin, alpha- and beta-catenins, plakophilin-2, desmoplakin-1, and desmocollin-2 at intercalated disks appeared normal.
  
  
  CONCLUSIONS
  Remodeling of gap junctions occurs early in Naxos disease, presumably because of abnormal linkage between mechanical junctions and the cytoskeleton. Gap junction remodeling may produce a coupling defect which, combined with the subsequent development of pathologic changes in myocardium, could contribute to a highly arrhythmogenic substrate and enhance the risk of sudden death in Naxos disease.
authors.affiliation: Department of Pathology and Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, Missouri 63100, USA.
authors.forename: Starr R
authors.initials: SR
authors.lastname: Kaplan
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Gard
authors.forename: Nikos
authors.initials: N
authors.lastname: Protonotarios
authors.forename: Adalena
authors.initials: A
authors.lastname: Tsatsopoulou
authors.forename: Chara
authors.initials: C
authors.lastname: Spiliopoulou
authors.forename: Aris
authors.initials: A
authors.lastname: Anastasakis
authors.forename: Catherine Prost
authors.initials: CP
authors.lastname: Squarcioni
authors.forename: William J
authors.initials: WJ
authors.lastname: McKenna
authors.forename: Gaetano
authors.initials: G
authors.lastname: Thiene
authors.forename: Cristina
authors.initials: C
authors.lastname: Basso
authors.forename: Nicole
authors.initials: N
authors.lastname: Brousse
authors.forename: Guy
authors.initials: G
authors.lastname: Fontaine
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Saffitz
mesh_terms: D000328:Adult; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D002886:Chromosomes, Human, Pair 17; D018031:Connexin 43 / Q000032:analysis* / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D017629:Gap Junctions / Q000235:genetics*; D006201:Hair Diseases / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D007365:Intercellular Junctions; D007645:Keratoderma, Palmoplantar / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009206:Myocardium; D032383:Myocytes, Cardiac; D017384:Sequence Deletion
chemical_list: D018031:Connexin 43; D003598:Cytoskeletal Proteins