Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy

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Item Type:	Article
Title:	Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy
Creators Name:	Heuser, A., Plovie, E.R., Ellinor, P.T., Grossmann, K.S., Shin, J.T., Wichter, T., Basson, C.T., Lerman, B.B., Sasse-Klaassen, S., Thierfelder, L., MacRae, C.A. and Gerull, B.
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-acceptorsite 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.
Keywords:	Amino Acid Sequence, Arrhythmogenic Right Ventricular Dysplasia, Base Sequence, Desmocollins, Nonmammalian Embryo, Molecular Sequence Data, Mutation, Myocardial Contraction, Animals, Zebrafish
Source:	American Journal of Human Genetics
ISSN:	0002-9297
Publisher:	University of Chicago Press
Volume:	79
Number:	6
Page Range:	1081-1088
Date:	December 2006
Official Publication:	https://doi.org/10.1086/509044
PubMed:	View item in PubMed

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