Background: According to the predominant view, desmin mutations cause dilated cardiomyopathy (DCM). We evaluated a family with restrictive cardiomyopathy (RCM) associated with a novel desmin mutation and reviewed recent reports regarding the frequency of RCM in patients with desmin myopathy.
Methods: Cardiovascular examination was performed in three affected and five at-risk members of a family from Poland, histopathologic study of skeletal muscle biopsy was done in a single patient, and functional analysis of mutant desmin protein was carried out in cultured cells.
Results: Cardiovascular assessment led to the diagnosis of RCM in affected family members. Histopathological study of skeletal muscle biopsy revealed features characteristic of desmin myopathy. A novel desmin E413K mutation was identified in each affected family member, but not unrelated controls. The pathogenicity of the E413K mutation was confirmed in transfected cell cultures showing inability of mutant desmin to form a cellular filamentous network or support a pre-existing network formed by other intermediate filaments. Three-dimensional modeling and electrostatic calculations indicated that the E413K mutation located in a functionally unique domain of desmin molecule potentially disrupts intramolecular interactions. Analysis of previously reported observations indicates that RCM in desminopathy patients may be as frequent as DCM.
Conclusions: A novel E413K mutation in desmin caused autosomal dominant RCM rather than DCM. The location of the E413K mutation at a highly conserved end of the alpha-helical rod domain may be related to the phenotypic differences from the previously described DCM-associated desmin mutations. Functional and structural analyses of mutant desmin allowed to identify likely pathogenic mechanisms.