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

## TL;DR

Scientists created a new mouse model for collagen VI-related muscle diseases, which can help test treatments and understand the condition better.

## Contribution

The study introduces a novel mouse model with a specific collagen VI mutation using CRISPR/Cas9, capturing a common human pathogenic variant.

## Key findings

- Knock-in mice showed early-onset muscle weakness, reduced weight, fibrosis, and impaired respiratory function.
- Automated image analysis methods enabled detailed characterization of muscle pathology in the model.
- The model provides reliable outcome measures for evaluating potential therapies for collagen VI-related dystrophies.

## 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.

Summary: Generation and characterization of a mouse model comprising dominant-negative glycine substitutions within collagen VI alpha chains, a frequent cause of collagen-VI-related dystrophies.