Atlas of cardiomyopathy associated DES (desmin) mutations: Focus on the 1B domain

Different cardiomyopathies like dilated, restrictive and arrhythmogenic cardiomyopathies can be caused by pathogenic mutations in the DES gene. The DES gene (OMIM, *125660) encodes the muscle specific intermediate filament (IF) protein desmin. In cardiomyocytes, the desmosomes are linked by desmoplakin with the IFs. The majority of known pathogenic DES mutations are missense or small in-frame deletion mutations. At the cellular level, an aberrant cytoplasmic desmin aggregation is typical for pathogenic desmin mutations. However, the majority of genetic variants are classified as ‘variants of unknown significance (VUS)’ since functional data on their pathogenicity are frequently missing. Therefore, we are generating an ‘Atlas of cardiomyopathy associated desmin variants’ based on the functional characterization of all known VUS in the DES gene, which are listed in public disease databases. Different cell lines and cardiomyocytes derived from induced pluripotent stem cells are transfected with desmin-wildtype or mutant desmin constructs and are analyzed by confocal microscopy in combination with deconvolution. In addition, we verify for selected variants the desmin filament assembly using atomic force microscopy. Using a proline screen, we identified a hotspot region in the desmin 1B domain, where different proline residues cause a filament assembly defect. The provided ‘Atlas of cardiomyopathy associated desmin mutations’ may be helpful for the clinical interpretation of rare DES variants in genetic diagnosis of non-ischemic cardiomyopathies.