ZFIN ID: ZDB-PUB-061229-25
Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy
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.
Date: 2006
Source: American journal of human genetics   79(6): 1081-1088 (Journal)
Registered Authors: Ellinor, Patrick, MacRae, Calum A., Shin, Jordan
Keywords: none
MeSH Terms:
  • Adult
  • Amino Acid Sequence
  • Animals
  • Arrhythmogenic Right Ventricular Dysplasia/genetics*
  • Arrhythmogenic Right Ventricular Dysplasia/pathology
  • Base Sequence
  • Desmocollins/genetics*
  • Desmocollins/metabolism
  • Embryo, Nonmammalian
  • Heart/embryology
  • Humans
  • Middle Aged
  • Molecular Sequence Data
  • Mutation*
  • Myocardial Contraction/genetics
  • Zebrafish/embryology
  • Zebrafish/genetics
PubMed: 17186466 Full text @ Am. J. Hum. Genet.
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.