Mutant desmocollin‑2 causes arrhythmogenic right ventricular cardiomyopathy (ARVC)

Desmosomes are complex multiprotein structures of the cell membrane and provide structural and functional integrity to adjacent cells, e.g. epithelial cells and cardiomyocytes. At least three groups of molecules contribute to the formation of desmosomes: desmosomal cadherins, arm repeat proteins and plakins. It has been previously shown, that mutations in desmosomal proteins cause arrhythmogenic right ventricular cardiomyopathy (ARVC) a genetically heterogeneous heart muscle disorder characterized by progressive fibro-fatty replacement of right ventricular myocardium and an increased risk of sudden cardiac death.

Now, Arnd Heuser, Brenda Gerull (laboratory of Ludwig Thierfelder), and collaborators have identified a new disease gene for ARVC, which encodes the desmosomal cadherin DSC2 (Am. J. Hum. Genet., 79:1081 – 1088, 2006 ). The researchers identified in a patient with ARVC a heterozygous splice acceptor site mutation in intron 5 (c.631 – 2A ® G) of the DSC2 gene, which led to use of a cryptic splice acceptor site and the creation of a downstream premature termination codon. Expression analyses in the affected patient suggest that DSC2 gene dose may contribute to the disease pathogenesis.

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 for ARVC in humans, and demonstrate that physiologic levels of DSC2 are crucial for normal cardiac desmosome formation, early cardiac morphogenesis and cardiac function.

Contact:

Pamela Cohen
p.​cohen@​mdc-​berlin.​de
+49 30 9406 2121