Col6a1 knock-in mice provide a promising pre-clinical model for collagen VI-related dystrophies
Por:
López-Marquez A, Badosa-Gallego MC, Enjuanes-Ruiz L, Hernández-Carabias P, Sánchez-Martín M, Cadot B, Guesmia Z, Georvasilis I, Balsells S, Blanco-Ramos M, Puighermanal E, Quintana A, Roldan-Molina M, Allamand V and Jimenez-Mallebrera C
Publicada:
1 ene 2025
Ahead of Print:
22 ene 2026
Resumen:
Collagen VI related dystrophies (COL6-RD) are congenital muscle diseases, typically inherited as an autosomal dominant trait. A frequent type of pathogenic variant involves glycine substitutions in the triple helical domain of collagen VI alpha chains, exerting a dominant-negative effect on the unaltered protein. Despite this, no prior animal model captured this mutation type. By using CRISPR/Cas9, we generated transgenic mice with the equivalent of the human COL6A1 c.877 G>A; p. Gly293Arg pathogenic variant. We characterized their skeletal muscle phenotype over time, utilizing computer-aided tools applied to standardized parameters of muscle pathology and function. Knock-in mice exhibited early-onset reduced muscle weight, myopathic histology, increased fibrosis, reduced collagen VI expression, muscle weakness and impaired respiratory function. These features provide adequate outcome measures to assess therapeutic interventions. Different automated image analysis methods deployed here are able analyze thousands of features simultaneously, enhancing accuracy in describing muscle disease models. Overall, the Col6a1 Ki Gly292Arg mouse model offers a robust platform to deepen our understanding of COL6-RD and advance its therapeutic landscape.
Filiaciones:
López-Marquez A:
Neuromuscular Unit, Neuropaediatrics Department, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
Center for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
Department of Genetics, Microbiology and Statistics. University of Barcelona, Spain
Badosa-Gallego MC:
Neuromuscular Unit, Neuropaediatrics Department, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
:
Neuromuscular Unit, Neuropaediatrics Department, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
Center for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
Hernández-Carabias P:
Instituto de Investigación Biomédica de Salamanca (IBSAL), Spain
Servicio de Transgénesis. Universidad de Salamanca, Spain
Sánchez-Martín M:
Instituto de Investigación Biomédica de Salamanca (IBSAL), Spain
Servicio de Transgénesis. Universidad de Salamanca, Spain
Cadot B:
Sorbonne Université-Inserm, Institut de Myologie, Centre de Recherche en Myologie, F-75013 Paris, France
Guesmia Z:
Sorbonne Université-Inserm, Institut de Myologie, Centre de Recherche en Myologie, F-75013 Paris, France
:
Confocal Microscopy and Cellular Imaging Unit, Department of Genetic and Molecular Medicine, Hospital Sant Joan de Déu, Barcelona, Spain. Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
Balsells S:
Statistics Department, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Blanco-Ramos M:
Institut de Neurociències, Universitat Autònoma de Barcelona, Spain
Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Spain
Puighermanal E:
Institut de Neurociències, Universitat Autònoma de Barcelona, Spain
Quintana A:
Institut de Neurociències, Universitat Autònoma de Barcelona, Spain
Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Spain
Roldan-Molina M:
Confocal Microscopy and Cellular Imaging Unit, Department of Genetic and Molecular Medicine, Hospital Sant Joan de Déu, Barcelona, Spain. Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
Allamand V:
Sorbonne Université-Inserm, Institut de Myologie, Centre de Recherche en Myologie, F-75013 Paris, France
Jimenez-Mallebrera C:
Neuromuscular Unit, Neuropaediatrics Department, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
Center for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
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