Copyright © 2006 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 79, Issue 6, 1081-1088, 1 December 2006
doi:10.1086/509044
Report
Mutant Desmocollin-2 Causes Arrhythmogenic Right Ventricular Cardiomyopathy
Arnd Heuser*, b, Eva R. Plovie*, c, Patrick T. Ellinorc, Katja S. Grossmann, Jordan T. Shinc, Thomas Wichterd, e, Craig T. Bassonf, Bruce B. Lermanf, Sabine Sasse-Klaassen, Ludwig Thierfelderb, Calum A. MacRaec and Brenda Gerullb, 
, 
a From the Max-Delbrueck Center for Molecular Medicine, Humboldt University, Berlin
b Department of Clinical and Molecular Cardiology, Franz-Volhard Clinic, HELIOS Clinics GmbH, Charité, Humboldt University, Berlin
c Cardiology Division and Cardiovascular Research Center, Massachusetts General Hospital, Boston
d Department of Cardiology and Angiology, University Hospital of Münster, Münster, Germany
e Institute for Arteriosclerosis Research at the University of Münster, Münster, Germany
f Greenberg Cardiology Division, Department of Medicine, Weill Medical College of Cornell University, New York
Address for correspondence and reprints: Dr. Brenda Gerull, Max-Delbrueck Center for Molecular Medicine, Robert-Roessle-Strasse 10, 13092 Berlin, Germany* These two authors contributed equally to this work.
Abstract
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically heterogeneous heart-muscle disorder characterized by progressive fibrofatty replacement of right ventricular myocardium and an increased risk of sudden cardiac death. Mutations in desmosomal proteins that cause ARVC have been previously described; therefore, we investigated 88 unrelated patients with the disorder for mutations in human desmosomal cadherin desmocollin-2 (DSC2). We identified a heterozygous splice-acceptor–site mutation in intron 5 (c.631-2A→G) of the DSC2 gene, which led to the use of a cryptic splice-acceptor site and the creation of a downstream premature termination codon. Quantitative analysis of cardiac DSC2 expression in patient specimens revealed a marked reduction in the abundance of the mutant transcript. Morpholino knockdown in zebrafish embryos revealed a requirement for dsc2 in the establishment of the normal myocardial structure and function, with reduced desmosomal plaque area, loss of the desmosome extracellular electron-dense midlines, and associated myocardial contractility defects. These data identify DSC2 mutations as a cause of ARVC in humans and demonstrate that physiologic levels of DSC2 are crucial for normal cardiac desmosome formation, early cardiac morphogenesis, and cardiac function.
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