G.P.8 05 Explorations on the molecular basis of desminopathy

Abstract

Mutations in the muscle-specific IF-protein desmin were recently demonstrated to cause severe forms of human skeletal and cardiac myopathy. Analogous to the situation in other IF-diseases, desmin-related myopathy is characterised by the formation of intracellular aggregates containing the IF-protein itself and associated proteins. By detailed in vitro analyses of more than 20 different recombinant pathogenic desmin mutants as well as transfection studies in different cellular surroundings we are able to demonstrate that the ability of mutant desmins to assemble into bona fide IFs and to form extended cellular networks varies considerably. In contrast to prior assumptions many mutations in fact do allow filament formation in vitro, and only these mutants are able to generate extended filamentous networks in transfected cells. Furthermore, only these latter mutants integrate into the endogenous vimentin network of 3T3 fibroblast cells. Assembly-incompetent mutants interrupt the assembly pathway at distinct stages in vitro, and, when transfected in fibroblasts, completely segregate from the vimentin system and cause this endogenous vimentin network to reorganize into perinuclear bundles.