title: Desmin mutations as a cause of right ventricular heart failure affect the intercalated disks.
abstract: BACKGROUND
  Mutations in the gene encoding desmin (DES), an intermediate filament protein, underlie a heterogeneous phenotype, which is referred to as desmin-related myopathy (DRM). Right ventricular involvement including an arrhythmogenic right ventricular cardiomyopathy (ARVC)(-like) phenotype has occasionally been described in DES mutation-carrying patients.
  
  
  OBJECTIVE
  To determine the effects of a DES missense mutation on the structure of different intercalated disk proteins, to evaluate right ventricular involvement in DES mutation carriers, and to establish the role of DES mutations in ARVC(-like) phenotypes.
  
  
  METHODS
  We evaluated the clinical phenotype in two families carrying two different DES mutations. One family was diagnosed with DRM, with an ARVC(-like) phenotype in one patient, while the other family presented with a severe biventricular cardiomyopathy. Additional immunohistochemistry of desmosomal proteins was performed in myocardial tissue from two patients of the last family. The DES gene was screened for mutations in 50 ARVC(-like) patients.
  
  
  RESULTS
  Except for two different DES mutations (p.N342D and p.R454W) in two families with DRM and severe biventricular cardiomyopathy, respectively, we did not find additional DES mutations in ARVC(-like) patients. In addition to desmin aggregates, immunohistochemistry demonstrated a decreased amount of desmoplakin and plakophilin-2 at the intercalated disk in p.R454W mutation carriers.
  
  
  CONCLUSIONS
  We confirmed that either an ARVC-like phenotype or a severe cardiomyopathy with right ventricular involvement are possible, yet infrequent, cardiac phenotypes in DRM. Moreover, we demonstrated that the DES mutation p.R454W affects the localization of desmoplakin and plakophilin-2 at the intercalated disk, suggesting a link between desmosomal cardiomyopathies (mainly affecting the right ventricle) and cardiomyopathies caused by DES mutations.
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, the Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: Otten
authors.forename: Angeliki
authors.initials: A
authors.lastname: Asimaki
authors.forename: Alexander
authors.initials: A
authors.lastname: Maass
authors.forename: Irene M
authors.initials: IM
authors.lastname: van Langen
authors.forename: Allard
authors.initials: A
authors.lastname: van der Wal
authors.forename: Nicolaas
authors.initials: N
authors.lastname: de Jonge
authors.forename: Maarten P
authors.initials: MP
authors.lastname: van den Berg
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Saffitz
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.forename: Jan D H
authors.initials: JD
authors.lastname: Jongbloed
authors.forename: J Peter
authors.initials: JP
authors.lastname: van Tintelen
mesh_terms: D000328:Adult; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000150:complications / Q000235:genetics; D009202:Cardiomyopathies / Q000150:complications / Q000235:genetics; D002648:Child; D003893:Desmin / Q000235:genetics*; D005260:Female; D006333:Heart Failure / Q000209:etiology / Q000235:genetics*; D006352:Heart Ventricles; D006579:Heterozygote; D006801:Humans; D007365:Intercellular Junctions / Q000502:physiology; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype
chemical_list: D003893:Desmin