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Background <p>Filaminopathies, caused by pathogenic <i>FLNC</i> variants, are rare neuromuscular disorders characterized by protein aggregation, z-disk pathology and lead to progressive muscle weakness and/or cardiomyopathies.</p> Methods <p>To address the lack of existing filaminopathy models in skeletal muscle, we developed a patient-specific cellular platform using induced pluripotent stem cells (iPSCs) harboring two truncating filamin C (FLNc) variants (p.Q1662X, p.Y2704X). Employing a developmental human skeletal muscle organoid hSMO model, we enrich for myogenic progenitor cells that are further differentiated into functional myotubes through 2D and 3D approaches (myotubes and musculoids).</p> Results <p>The 2D myotubes exhibited poor sarcomeric organization and hallmarks of filaminopathies, including protein aggregation and proteostatic dysfunction, marked by elevated aggresome formation and an increased basal autophagic flux. The 3D musculoids revealed ultrastructural abnormalities and enabled the identification of novel disease-associated proteins involved in ER stress and protein folding (e.g. DNAJC10) through proteomic analysis. Proteomic findings were additionally validated in 2D cultures and in corresponding patient-derived muscle biopsies enhancing the model’s translational value.</p> Conclusions <p>Our model is suitable to monitor aspects of filaminopathies’ pathogenesis and to investigate possible therapeutic interventions with quantitative readouts.</p>

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Unveiling FLNC variants: iPSC-derived myogenic cells as a model to study disease mechanisms

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月12日

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  • Nassam M. Daya,
  • Anne Schänzer,
  • Andreas Hentschel,
  • Marie-Cecile Kienitz,
  • Dominik Sellung,
  • Nicolina Suedkamp,
  • Karsten Krause,
  • Jaqueline C. Kinold,
  • Leon Volke,
  • Anja Schreiner,
  • Hanna Schlierbach,
  • Christopher Nelke,
  • Felix Kleefeld,
  • Anne-Katrin Guettsches,
  • Holm Zaehres,
  • Tobias Ruck,
  • Lampros Mavrommatis,
  • Andreas Roos,
  • Matthias Vorgerd

摘要

Background

Filaminopathies, caused by pathogenic FLNC variants, are rare neuromuscular disorders characterized by protein aggregation, z-disk pathology and lead to progressive muscle weakness and/or cardiomyopathies.

Methods

To address the lack of existing filaminopathy models in skeletal muscle, we developed a patient-specific cellular platform using induced pluripotent stem cells (iPSCs) harboring two truncating filamin C (FLNc) variants (p.Q1662X, p.Y2704X). Employing a developmental human skeletal muscle organoid hSMO model, we enrich for myogenic progenitor cells that are further differentiated into functional myotubes through 2D and 3D approaches (myotubes and musculoids).

Results

The 2D myotubes exhibited poor sarcomeric organization and hallmarks of filaminopathies, including protein aggregation and proteostatic dysfunction, marked by elevated aggresome formation and an increased basal autophagic flux. The 3D musculoids revealed ultrastructural abnormalities and enabled the identification of novel disease-associated proteins involved in ER stress and protein folding (e.g. DNAJC10) through proteomic analysis. Proteomic findings were additionally validated in 2D cultures and in corresponding patient-derived muscle biopsies enhancing the model’s translational value.

Conclusions

Our model is suitable to monitor aspects of filaminopathies’ pathogenesis and to investigate possible therapeutic interventions with quantitative readouts.