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Open Access Research article

Missense mutations in Desmocollin-2 N-terminus, associated with arrhythmogenic right ventricular cardiomyopathy, affect intracellular localization of desmocollin-2 in vitro

Giorgia Beffagna1, Marzia De Bortoli1, Andrea Nava2, Michela Salamon1, Alessandra Lorenzon1, Manuela Zaccolo3, Luisa Mancuso3, Luca Sigalotti4, Barbara Bauce2, Gianluca Occhi1, Cristina Basso5, Gerolamo Lanfranchi16, Jeffrey A Towbin7, Gaetano Thiene5, Gian Antonio Danieli1 and Alessandra Rampazzo1*

Author Affiliations

1 Department of Biology, University of Padua, Padua, Italy

2 Department of Cardiothoracic-Vascular Sciences, University of Padua Medical School, Padua, Italy

3 Venetian Institute of Molecular Medicine, Padua, Italy

4 Cancer Bioimmunotherapy Unit, Department of Medical Oncology, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy

5 Institute of Pathology, University of Padua, Padua, Italy

6 CRIBI Biotecnology Centre, University of Padua, Padua, Italy

7 Department of Pediatrics, Section of Cardiology, Baylor College of Medicine, Houston, Texas, USA

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BMC Medical Genetics 2007, 8:65  doi:10.1186/1471-2350-8-65

Published: 26 October 2007



Mutations in genes encoding desmosomal proteins have been reported to cause arrhythmogenic right ventricular cardiomyopathy (ARVC), an autosomal dominant disease characterised by progressive myocardial atrophy with fibro-fatty replacement.

We screened 54 ARVC probands for mutations in desmocollin-2 (DSC2), the only desmocollin isoform expressed in cardiac tissue.


Mutation screening was performed by denaturing high-performance liquid chromatography and direct sequencing.

To evaluate the pathogenic potentials of the DSC2 mutations detected in patients affected with ARVC, full-length wild-type and mutated cDNAs were cloned in eukaryotic expression vectors to obtain a fusion protein with green fluorescence protein (GFP); constructs were transfected in neonatal rat cardiomyocytes and in HL-1 cells.


We identified two heterozygous mutations (c.304G>A (p.E102K) and c.1034T>C (p.I345T)) in two probands and in four family members. The two mutations p.E102K and p.I345T map to the N-terminal region, relevant to adhesive interactions.

In vitro functional studies demonstrated that, unlike wild-type DSC2, the two N-terminal mutants are predominantly localised in the cytoplasm.


The two missense mutations in the N-terminal domain affect the normal localisation of DSC2, thus suggesting the potential pathogenic effect of the reported mutations. Identification of additional DSC2 mutations associated with ARVC may result in increased diagnostic accuracy with implications for genetic counseling.