PUBLICATION
Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy
- Authors
- 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.
- ID
- ZDB-PUB-061229-25
- 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
-
- Molecular Sequence Data
- Arrhythmogenic Right Ventricular Dysplasia/genetics*
- Arrhythmogenic Right Ventricular Dysplasia/pathology
- Desmocollins/genetics*
- Desmocollins/metabolism
- Amino Acid Sequence
- Humans
- Embryo, Nonmammalian
- Adult
- Mutation*
- Zebrafish/embryology
- Zebrafish/genetics
- Heart/embryology
- Middle Aged
- Myocardial Contraction/genetics
- Base Sequence
- Animals
- PubMed
- 17186466 Full text @ Am. J. Hum. Genet.
Citation
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. (2006) Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy. American journal of human genetics. 79(6):1081-1088.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping