%0 Journal Article %J Circ Res %D 2006 %T Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy. %A Yang, Zhao %A Bowles, Neil E %A Steven E Scherer %A Taylor, Michael D %A Kearney, Debra L %A Ge, Shuping %A Nadvoretskiy, Vyacheslav V %A DeFreitas, Gilberto %A Carabello, Blasé %A Brandon, Lois I %A Godsel, Lisa M %A Green, Kathleen J %A Saffitz, Jeffrey E %A Li, Hua %A Danieli, Gian Antonio %A Calkins, Hugh %A Marcus, Frank %A Towbin, Jeffrey A %K Animals %K Apoptosis %K Arrhythmogenic Right Ventricular Dysplasia %K Cardiomyopathies %K Cell Communication %K Cell Line, Tumor %K Desmoplakins %K Desmosomes %K DNA Mutational Analysis %K Embryo, Mammalian %K Heart %K Humans %K Intercellular Junctions %K Lipid Metabolism %K Mice %K Mice, Transgenic %K Mutation, Missense %K Myocytes, Cardiac %X

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.

%B Circ Res %V 99 %P 646-55 %8 2006 Sep 15 %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/16917092?dopt=Abstract %R 10.1161/01.RES.0000241482.19382.c6