title: Desmoglein 2 mutant mice develop cardiac fibrosis and dilation.
abstract: Desmosomes are cell-cell adhesion sites and part of the intercalated discs, which couple adjacent cardiomyocytes. The connection is formed by the extracellular domains of desmosomal cadherins that are also linked to the cytoskeleton on the cytoplasmic side. To examine the contribution of the desmosomal cadherin desmoglein 2 to cardiomyocyte adhesion and cardiac function, mutant mice were prepared lacking a part of the extracellular adhesive domain of desmoglein 2. Most live born mutant mice presented normal overall cardiac morphology at 2 weeks. Some animals, however, displayed extensive fibrotic lesions. Later on, mutants developed ventricular dilation leading to cardiac insufficiency and eventually premature death. Upon histological examination, cardiomyocyte death by calcifying necrosis and replacement by fibrous tissue were observed. Fibrotic lesions were highly proliferative in 2-week-old mutants, whereas the fibrotic lesions of older mutants showed little proliferation indicating the completion of local muscle replacement by scar tissue. Disease progression correlated with increased mRNA expression of c-myc, ANF, BNF, CTGF and GDF15, which are markers for cardiac stress, remodeling and heart failure. Taken together, the desmoglein 2-mutant mice display features of dilative cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy, an inherited human heart disease with pronounced fibrosis and ventricular arrhythmias that has been linked to mutations in desmosomal proteins including desmoglein 2.
authors: Institute of Molecular and Cellular Anatomy, RWTH Aachen University, Wendlingweg 2, Aachen, Germany. ckrusche@ukaachen.de
authors: Claudia A
authors: CA
authors: Krusche
authors: Bastian
authors: B
authors: Holthöfer
authors: Valérie
authors: V
authors: Hofe
authors: Annette M
authors: AM
authors: van de Sandt
authors: Leonid
authors: L
authors: Eshkind
authors: Ernesto
authors: E
authors: Bockamp
authors: Marc W
authors: MW
authors: Merx
authors: Sebastian
authors: S
authors: Kant
authors: Reinhard
authors: R
authors: Windoffer
authors: Rudolf E
authors: RE
authors: Leube
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000209:etiology; D051301:Desmoglein 2 / Q000502:physiology*; D004108:Dilatation, Pathologic; D005260:Female; D005355:Fibrosis; D055436:Growth Differentiation Factor 15 / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009206:Myocardium / Q000473:pathology*
chemical_list: D051301:Desmoglein 2; C495315:Dsg2 protein, mouse; C526141:Gdf15 protein, mouse; D055436:Growth Differentiation Factor 15