<i>Col6a1</i> knock-in mice provide a promising pre-clinical model for collagen VI-related dystrophies

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.

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Publication Details

Journal
Disease Models & Mechanisms
Published
2025-11-25
DOI
https://doi.org/10.1242/dmm.052460
Primary Topic
Muscle Physiology and Disorders
Type
article
Field-Weighted Citation Impact
0.00

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article

Col6a1 knock-in mice provide a promising pre-clinical model for collagen VI-related dystrophies

C. Jimenez‐Mallebrera, Bruno Cadot, Emma Puighermanal, Zoheir Guesmia et al.
Disease Models & Mechanisms
Muscle Physiology and Disorders
article

Col6a1 knock-in mice provide a promising pre-clinical model for collagen VI-related dystrophies

C. Jimenez‐Mallebrera, Bruno Cadot, Emma Puighermanal, Zoheir Guesmia, Albert Quintana, Valérie Allamand, Patricia Hernández‐Carabias, Arístides López‐Márquez, Mónica Roldán, Carmen Badosa, Sol Balsells, Manuel Sánchez‐Martín, Marcos Blanco-Ramos, Ioannis Georvasilis, Lluis Enjuanes-Ruiz
article en

Abstract

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.

Disease Models & MechanismsVol. 19(1)
Universitat Autònoma de Barcelona (ES), Hospital Sant Joan de Déu Barcelona (ES), Inserm (FR), Universidad de Salamanca (ES), Instituto de Salud Carlos III (ES), Sorbonne Université (FR), Centre for Biomedical Network Research on Rare Diseases (ES), Institut de Myologie (FR), Sant Joan de Déu Research Foundation (ES), Instituto de Investigación Biomédica de Salamanca (ES), Centre de Recherche en Myologie, Universitat de Barcelona (ES)
Alexion Pharmaceuticals, European Commission, Institut National de la Santé et de la Recherche Médicale, Instituto de Salud Carlos III
Openalex Percentile: Top 67%
Muscle Physiology and Disorders
DOIOpen Access PDFOpenAlex
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