A missense mutation (Ile 451 to Met) at the tail domain of the muscle-specific intermediate filament
protein desmin has been suggested to be a genetic cause of
dilated cardiomyopathy. The Ile451Met mutation is located inside a conserved motif in the
desmin tail domain, believed to have a potential role in the lateral packing of type III intermediate filaments. Nevertheless, the role of the type III intermediate filament tail domain remains elusive. To further study the role of this domain in the function of cardiomyocytes and in the development of
cardiomyopathy, we generated transgenic mice expressing the mutant
desmin(I451M) in the cardiac tissue. Analysis of hearts from transgenic animals revealed that mutant
desmin loses its Z-disc localization but it can still associate with the intercalated discs, which, however, have an altered architecture, resembling other examples of
dilated cardiomyopathy. This is the first report demonstrating a critical role of the
desmin head and tail domains in the formation of the IF scaffold around Z discs. It is further suggested that in cardiomyocytes, an interplay between
desmin tail and head domains is taking place, which potentially protects the amino terminus of
desmin from specific
proteases. The fact that the association with intercalated discs seems unchanged suggests that this association must take place through the
desmin tail, in contrast to the head domain that is most possibly involved in the Z-disc binding.