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Am J Hum Genet. 2006 Dec;79(6):1081-8. Epub 2006 Oct 3.

Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy.

Author information

1
Max-Delbrueck Center for Molecular Medicine, Franz-Volhard Clinic, HELIOS Clinics GmbH, Charité, Humboldt University, Berlin, Germany.

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.

PMID:
17186466
PMCID:
PMC1698714
DOI:
10.1086/509044
[Indexed for MEDLINE]
Free PMC Article

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