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Updated: Feb 14, 2026

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
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Unveiling FLNC variants: iPSC-derived myogenic cells as a model to study disease mechanisms

Nassam M Daya1,2, Anne Schänzer3,4, Andreas Hentschel5

  • 1Ruhr University Bochum, BG University Hospital Bergmannsheil, Department of Neurology, Bochum, Germany, Ruhr-University Bochum, Bochum, Germany. nassam.daya@rub.de.

Skeletal Muscle
|February 12, 2026
PubMed
Abstract

Insights

Researchers developed a patient-specific skeletal muscle organoid model for filaminopathies, rare neuromuscular disorders. This model reveals disease hallmarks and aids in identifying therapeutic targets for filamin C (FLNC) related muscle weakness and cardiomyopathies.

Area of Science:

  • * Neuromuscular Biology
  • * Stem Cell Biology
  • * Disease Modeling

Background:

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

Purpose of the Study:

  • * To develop a patient-specific cellular platform for studying filaminopathies in skeletal muscle.
  • * To create a human skeletal muscle organoid (hSMO) model for filaminopathy research.

Main Methods:

  • * Utilized induced pluripotent stem cells (iPSCs) from patients with truncating FLNC variants (p.Q1662X, p.Y2704X).
  • * Developed hSMO models, enriching for myogenic progenitor cells differentiated into 2D myotubes and 3D musculoids.

Main Results:

  • * 2D myotubes showed poor sarcomeric organization, protein aggregation, and proteostatic dysfunction.
  • * 3D musculoids displayed ultrastructural abnormalities and identified novel disease-associated proteins (e.g., DNAJC10) via proteomic analysis.
  • * Proteomic findings were validated in 2D cultures and patient muscle biopsies.

Conclusions:

  • * The developed model effectively recapitulates key aspects of filaminopathy pathogenesis.
  • * This model serves as a valuable tool for investigating therapeutic interventions with quantitative readouts.
Keywords:
Disease modelingFilaminopathiesOrganoidiPSC

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