Characterization of <i>DMPK</i> and MBNL1 expression in cell models of myotonic dystrophy: a platform for drug screening
Myotonic dystrophy type I (DM1) is caused by CTG repeat expansions in the <i>DMPK</i> gene leading to mRNA toxicity and sequestration of the splicing regulator MBNL1, affecting many tissues. We have developed an <i>in vitro</i> screening platform based on ddPCR and in-cell western to quantify these mRNAs and proteins and characterized >20 cell models to define DM1 biomarkers that could be useful for drug screening. DMPK protein levels were reduced in DM1-immortalized myoblasts and myotubes, but not in fibroblasts, while MBNL1 protein was consistently lower in all DM1 myogenic cultures, whether primary or immortalized. Myogenic differentiation of cultures led to an increase in <i>DMPK</i> mRNA expression, which was translated into increased MBNL1 sequestration in foci. We further corroborated the platform's ability to assess therapeutic outcomes, evaluating the effect of a DMPK gapmer ASO and one siRNA: while the gapmer increased MBNL1 protein levels, the siRNA had no significant effect on MBNL1 release. Our platform and the in-depth characterization of some of the most used models would be of use to the DM1 research community.
Authors
- Gisela Nogales‐Gadea (ORCID: https://orcid.org/0000-0002-7414-212X)
- Kamel Mamchaoui (ORCID: https://orcid.org/0000-0002-0323-9290)
- Anne Bigot (ORCID: https://orcid.org/0000-0003-0337-5425)
- A.A. أحمد علاء الدين طه Al-Ani (ORCID: https://orcid.org/0000-0003-4567-4837)
- Andrea López‐Martínez (ORCID: https://orcid.org/0000-0003-4711-7495)
- Virginia Arechavala‐Gomeza (ORCID: https://orcid.org/0000-0001-7703-3255)
- Noemi Torres‐Conde
- Sergio Martín‐González
- Adolfo López de Munain
- Nahia Alcalá-Manso
Institutions
- Ikerbasque (ES)
- Universidad de Deusto (ES)
- Inserm (FR)
- University of the Basque Country (ES)
- Instituto de Salud Carlos III (ES)
- Sorbonne Université (FR)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- BioCruces Health research Institute (ES)
- Biogipuzkoa Health Research Institute (ES)
- Institut de Myologie (FR)
- Ministry of Science (ME)
- Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (ES)
- Donostiako Unibertsitate Ospitalea (ES)
- Centre de Recherche en Myologie
Publication Details
- Journal
- NAR Molecular Medicine
- Published
- 2025-06-20
- DOI
- https://doi.org/10.1093/narmme/ugaf023
- Citations
- 1
- Primary Topic
- Genetic Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.91
Funders
- Muscular Dystrophy Association
- European Commission
- Radboud Universiteit
- Ikerbasque, Basque Foundation for Science
- Radboud Universitair Medisch Centrum
- Instituto de Salud Carlos III
- Agencia Estatal de Investigación