Mutations in desmin have been associated with a subset of human myopathies. 
Symptoms typically appear in the second to third decades of life, but in the 
most severe cases can manifest themselves earlier. How desmin mutations lead to 
aberrant muscle function, however, remains poorly defined. We created a series 
of four mutations in rat desmin and tested their in vitro filament assembly 
properties. RDM-G, a chimera between desmin and green fluorescent protein, 
formed protofilament-like structures in vitro. RDM-1 and RDM-2 blocked in vitro 
assembly at the unit-length filament stage, while RDM-3 had more subtle effects 
on assembly. When expressed in cultured rat neonatal cardiac myocytes via 
adenovirus infection, these mutant proteins disrupted the endogenous desmin 
filament to an extent that correlated with their defects in in vitro assembly 
properties. Disruption of the desmin network by RDM-1 was also associated with 
disruption of plectin, myosin, and alpha-actinin organization in a significant 
percentage of infected cells. In contrast, expression of RDM-2, which is similar 
to previously characterized human mutant desmins, took longer to disrupt desmin 
and plectin organization and had no significant effect on myosin or 
alpha-actinin organization over the 5-day time course of our studies. RDM-3 had 
the mildest effect on in vitro assembly and no discernable effect on either 
desmin, plectin, myosin, or alpha-actinin organization in vivo. These results 
indicate that mutations in desmin have both direct and indirect effects on the 
cytoarchitecture of cardiac myocytes.