The myofibrillar myopathy-linked variant DES-p.T341P impairs desmin filament assembly.

BACKGROUND: Desminopathies are clinical heterogenous and range from isolated skeletal myopathies to different cardiomyopathies or combinations of both. At the molecular level, an aberrant cytoplasmic desmin aggregation is a typical hallmark of pathogenic DES variants. Currently, it is difficult to predict an aberrant desmin aggregation of novel DES variants without functional analysis. METHODS: Therefore, we investigate in this study the impact of an uncharacterized myofibrillar myopathy-associated desmin variant (p.T341P) on filament assembly in transfected cells and performed atomic force microscopy to characterize in vitro the filament assembly of recombinant desmin-p.T341P. RESULTS: Based on these cell transfection experiments using different cell lines and cardiomyocytes differentiated from induced pluripotent stem cells (iPSC) we present evidence that the filament assembly of desmin-p.T341P is disrupted. In addition, atomic force microscopy (AFM) analysis revealed aberrant molecular structures of recombinant desmin in comparison to wild-type desmin. These experiments showed an intrinsic filament assembly defect of desmin-p.T341P. Therefore, we suggest to classify this DES variant as a likely pathogenic variant associated with myofibrillar myopathy and heart failure. CONCLUSION: In conclusion, functional analysis of the desmin filament assembly can contribute to the pathogenicity classification of further DES variants and may be helpful in genetic counselling of affected patients.