2025/11/25 by Arístides López‐Márquez, Carmen Badosa, Lluis Enjuanes-Ruiz +12 · 1 voice · 1 citation
Biochemistry, Genetics and Molecular Biology · Medicine · #Cell Adhesion Molecules Research #Cellular Mechanics and Interactions #Muscle Physiology and Disorders
paper · pdf · doi:10.1242/dmm.052460
openalex created_date 2025/11/25 · openalex publication_date 2025/11/25 · openalex updated_date 2026/07/31
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.