Published online before print August 17, 2006, doi: 10.1161/01.RES.0000241482.19382.c6
© 2006 American Heart Association, Inc.
Integrative Physiology |
Desmosomal Dysfunction due to Mutations in Desmoplakin Causes Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy
From the Departments of Medicine, Cardiovascular Sciences (Z.Y., J.A.T.) and General Medicine (G.D., B.C.), Pediatrics (Cardiology) (N.E.B., M.D.T., S.G., V.V.N., L.I.B., H.L., J.A.T.), Molecular and Human Genetics (S.E.S., J.A.T.), and Pathology (D.L.K.), Baylor College of Medicine, Houston, Tex; the Departments of Pathology and Dermatology (L.M.G., K.J.G.), Northwestern University Feinberg School of Medicine, Chicago, Ill; the Department of Pathology (J.E.S.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass; the Department of Biology (G.A.D.), University of Padua Medical School, Padua, Italy; Department of Cardiology (H.C.), Johns Hopkins School of Medicine, Baltimore, Md; and the Department of Medicine (F.M.), University of Arizona, Tucson, Ariz.
Correspondence to Jeffrey A. Towbin, MD, Department of Pediatrics (Cardiology), Baylor College of Medicine, Texas Children’s Hospital, 6621 Fannin, MC 19345-C, Houston, TX 77030. E-mail jtowbin{at}bcm.tmc.edu
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.
Key Words: arrhythmogenic right ventricular dysplasia/cardiomyopathy • mechanical junctions • gene mutations
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