title: Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy.
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.
authors.affiliation: Max-Delbrueck Center for Molecular Medicine, Franz-Volhard Clinic, HELIOS Clinics GmbH, Charité, Humboldt University, Berlin, Germany.
authors.forename: Arnd
authors.initials: A
authors.lastname: Heuser
authors.forename: Eva R
authors.initials: ER
authors.lastname: Plovie
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Ellinor
authors.forename: Katja S
authors.initials: KS
authors.lastname: Grossmann
authors.forename: Jordan T
authors.initials: JT
authors.lastname: Shin
authors.forename: Thomas
authors.initials: T
authors.lastname: Wichter
authors.forename: Craig T
authors.initials: CT
authors.lastname: Basson
authors.forename: Bruce B
authors.initials: BB
authors.lastname: Lerman
authors.forename: Sabine
authors.initials: S
authors.lastname: Sasse-Klaassen
authors.forename: Ludwig
authors.initials: L
authors.lastname: Thierfelder
authors.forename: Calum A
authors.initials: CA
authors.lastname: MacRae
authors.forename: Brenda
authors.initials: B
authors.lastname: Gerull
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D051187:Desmocollins / Q000235:genetics* / Q000378:metabolism; D004625:Embryo, Nonmammalian; D006321:Heart / Q000196:embryology; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009200:Myocardial Contraction / Q000235:genetics; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
chemical_list: C081561:DSC2 protein, human; D051187:Desmocollins