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Mutated Desmoglein-2 Proteins are Incorporated into Desmosomes and Exhibit Dominant-Negative Effects in Arrhythmogenic Right Ventricular Cardiomyopathy

Authors


  • Additional Supporting Information may be found in the online version of this article.

  • Communicated by Reed Pyeritz

  • Contract grant sponsors: The Research Foundation of Central Denmark Region; The Lundbeck Foundation; Arvid Nilsson's Foundation; The Faculty of Health Sciences, Aarhus University; Helga and Peter Korning's Foundation; Torben & Alice Frimodt's Foundation; John and Birthe Meyer Foundation; Karen Elise Jensen's Foundation; Bønnelycke's Foundation; Niels Jensen's Research Foundation; Hospital of Vendsyssel; INHERITANCE (Integrated Heart Research In Translational Genetics of Cardiomyopathies in Europe) (291924).

Corresponding to: Jens Mogensen, Odense University Hospital, Department of Cardiology, Sdr. Boulevard 29, DK-5000 Odense C, Denmark. E-mail: jens.mogensen@dadlnet.dk

ABSTRACT

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary cardiac condition associated with ventricular arrhythmias, heart failure, and sudden death. The most frequent ARVC genes encode desmosomal proteins of which mutations in desmoglein-2 (DSG2), account for 10%–20% of cases. This study aimed to investigate how DSG2 mutations contribute to the pathogenesis of ARVC. Initial mutation analysis of DSG2 in 71 probands identified the first family reported with recessively inherited ARVC due to a missense mutation. In addition, three recognized DSG2 mutations were identified in 12 families. These results and further mutation analyses of four additional desmosomal genes indicated that ARVC caused by DSG2 mutations is often transmitted by recessive or digenic inheritance. Because desmosomal proteins are also expressed in skin tissue, keratinocytes served as a cell model to investigate DSG2 protein expression by Western blotting, 2D-PAGE, and liquid chromatography–mass spectrometry. The results showed that heterozygous mutation carriers expressed both mutated and wild-type DSG2 proteins. These findings were consistent with the results obtained by immunohistochemistry of endomyocardial biopsies and epidermal tissue of mutation carriers, which indicated a normal cellular distribution of DSG2. The results suggested a dominant-negative effect of the mutated DSG2 proteins because they were incorporated into the desmosomes.

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