Brodehl, A. | Search bioRxiv

bioRxiv2026

The DES-p.A120P mutation associated with biventricular arrhythmogenic cardiomyopathy has a dominant-negative effect on desmin filament assembly

Desmin is a muscle-specific intermediate filament protein, which connects different cell organelles and is highly relevant for the structural integrity of cardiomyocytes. Mutations in the DES gene, cause different cardiomyopathies including arrhythmogenic cardiomyopathy. In this study, we functionally investigate the novel genetic variant DES-p.A120P using cell transfection experiments including cardiomyocytes derived from induced pluripotent stem cells in combination with confocal microscopy. These experiments reveal that the filament assembly of desmin-p.A120P is disturbed - even when co-expressed with wild-type desmin. In conclusion, the functional characterization of desmin-p.A120P supports the classification as a pathogenic variant associated with arrhythmogenic cardiomyopathy.

genetics↗

bioRxiv2023

Atlas of DES (desmin) variants: Impact of variants located within the head domain on filament assembly

Desmin is a muscle-specific intermediate filament protein, which plays a significant role in providing structural integrity of cardiomyocytes by connecting different cell organelles and multi-protein complexes. DES mutations cause cardiomyopathies and skeletal myopathies. Most of these pathogenic mutations are localized in the highly conserved rod domain and affect the filament assembly. However, the impact of DES variants within the N-terminal head domain on the filament assembly process is widely unknown. Therefore, we inserted a set of 85 different head domain variants with unknown significance from human genetic databases in expression constructs and investigated their impact on filament formation in cell culture in combination with confocal microscopy. The majority of these desmin variants do not affect the filament assembly. However, the desmin variants -p.S13P, -p.N107D, -p.E108G and -p.K109E significantly inhibit the filament assembly. Additionally, we expressed and purified recombinant desmin and investigated the filament assembly defects by atomic force microscopy verifying these findings at the single molecular level. Furthermore, we truncated systematically the head domain to investigate which general parts of this domain are necessary for filament assembly. In summary, our functional investigations might be relevant for the classification of novel DES variants and the genetic counselling of patients carrying desmin head variants.

cell biology↗