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Background <p>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 <i>DES</i> variants. Currently, it is difficult to predict an aberrant desmin aggregation of novel <i>DES</i> variants without functional analysis.</p> Methods <p>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.</p> Results <p>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 <i>DES</i> variant as a likely pathogenic variant associated with myofibrillar myopathy and heart failure.</p> Conclusion <p>In conclusion, functional analysis of the desmin filament assembly can contribute to the pathogenicity classification of further <i>DES</i> variants and may be helpful in genetic counselling of affected patients.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月25日

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  • Alexander Lütkemeyer,
  • Sabrina Voß,
  • Franziska Klag,
  • Joline Groß,
  • Jonas Reckmann,
  • Anna Gärtner,
  • Dario Anselmetti,
  • Jan Gummert,
  • Volker Walhorn,
  • Hendrik Milting,
  • Andreas Brodehl

摘要

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.