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

Abstract

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.

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