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

TL;DR

This study shows that a specific genetic variant in desmin disrupts its ability to form filaments, leading to myofibrillar myopathy and heart failure.

Contribution

The study identifies a novel pathogenic DES variant (p.T341P) by demonstrating its impact on desmin filament assembly using cell and in vitro experiments.

Findings

Desmin-p.T341P shows disrupted filament assembly in transfected cells and cardiomyocytes.

Atomic force microscopy reveals aberrant molecular structures in recombinant desmin-p.T341P.

The variant is classified as likely pathogenic due to intrinsic filament assembly defects.

Abstract

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.

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.

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.

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.

The online version contains supplementary material available at 10.1007/s11033-026-11696-z.

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