Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy.
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.
Heuser
Arnd
A
Max-Delbrueck Center for Molecular Medicine, Franz-Volhard Clinic, HELIOS Clinics GmbH, Charité, Humboldt University, Berlin, Germany.
Plovie
Eva R
ER
Ellinor
Patrick T
PT
Grossmann
Katja S
KS
Shin
Jordan T
JT
Wichter
Thomas
T
Basson
Craig T
CT
Lerman
Bruce B
BB
Sasse-Klaassen
Sabine
S
Thierfelder
Ludwig
L
MacRae
Calum A
CA
Gerull
Brenda
B
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
C081561:DSC2 protein, human; D051187:Desmocollins