title: Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy.
abstract: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by progressive degeneration of the right ventricular myocardium, ventricular arrhythmias, fibrous-fatty replacement, and increased risk of sudden death. Mutations in 6 genes, including 4 encoding desmosomal proteins (Junctional plakoglobin (JUP), Desmoplakin (DSP), Plakophilin 2, and Desmoglein 2), have been identified in patients with ARVD/C. Mutation analysis of 66 probands identified 4 variants in DSP; V30M, Q90R, W233X, and R2834H. To establish a cause and effect relationship between those DSP missense mutations and ARVD/C, we performed in vitro and in vivo analyses of the mutated proteins. Unlike wild-type (WT) DSP, the N-terminal mutants (V30M and Q90R) failed to localize to the cell membrane in desomosome-forming cell line and failed to bind to and coimmunoprecipitate JUP. Multiple attempts to generate N-terminal DSP (V30M and Q90R) cardiac-specific transgenes have failed: analysis of embryos revealed evidence of profound ventricular dilation, which likely resulted in embryonic lethality. We were able to develop transgenic (Tg) mice with cardiac-restricted overexpression of the C-terminal mutant (R2834H) or WT DSP. Whereas mice overexpressing WT DSP had no detectable histologic, morphological, or functional cardiac changes, the R2834H-Tg mice had increased cardiomyocyte apoptosis, cardiac fibrosis, and lipid accumulation, along with ventricular enlargement and cardiac dysfunction in both ventricles. These mice also displayed interruption of DSP-desmin interaction at intercalated discs (IDs) and marked ultra-structural changes of IDs. These data suggest DSP expression in cardiomyocytes is crucial for maintaining cardiac tissue integrity, and DSP abnormalities result in ARVD/C by cardiomyocyte death, changes in lipid metabolism, and defects in cardiac development.
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Yang
authors.forename: Neil E
authors.initials: NE
authors.lastname: Bowles
authors.forename: Steven E
authors.initials: SE
authors.lastname: Scherer
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Debra L
authors.initials: DL
authors.lastname: Kearney
authors.forename: Shuping
authors.initials: S
authors.lastname: Ge
authors.forename: Vyacheslav V
authors.initials: VV
authors.lastname: Nadvoretskiy
authors.forename: Gilberto
authors.initials: G
authors.lastname: DeFreitas
authors.forename: Blasé
authors.initials: B
authors.lastname: Carabello
authors.forename: Lois I
authors.initials: LI
authors.lastname: Brandon
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Godsel
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Green
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Saffitz
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Gian Antonio
authors.initials: GA
authors.lastname: Danieli
authors.forename: Hugh
authors.initials: H
authors.lastname: Calkins
authors.forename: Frank
authors.initials: F
authors.lastname: Marcus
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Towbin
mesh_terms: D000818:Animals; D017209:Apoptosis; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000209:etiology*; D009202:Cardiomyopathies / Q000209:etiology*; D002450:Cell Communication / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D051180:Desmoplakins / Q000235:genetics*; D003896:Desmosomes / Q000235:genetics / Q000502:physiology*; D004622:Embryo, Mammalian; D006321:Heart / Q000254:growth & development; D006801:Humans; D007365:Intercellular Junctions / Q000473:pathology; D050356:Lipid Metabolism; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D032383:Myocytes, Cardiac / Q000473:pathology / Q000648:ultrastructure*
chemical_list: D051180:Desmoplakins