Development, validation, and preliminary phenotypic characterization of a Col6a3 knockout mouse model targeting exon 3.

Abstract

BACKGROUND: Most mutations in the COL6A3 gene lead to collagen VI-related myopathies. This is due to a reduced expression or mislocalization of the COL6A3 protein. Therefore, studying the consequence of knocking out the Col6a3 gene in mouse models is relevant, but the Col6a3 mouse models reported so far do not entirely abolish COL6A3 protein expression. METHODS: Here, we present the development, validation and preliminary phenotypic characterization of a novel CRISPR-based knockout mouse model targeting Col6a3 exon 3 (Col6a3). RESULTS: In this mouse model, Col6a3 mRNA is still expressed at a similar level to wild-type littermates, although the expected protein is undetectable by mass spectrometry. Histological analysis of Col6a3quadriceps revealed an abnormally high frequency of muscle cells with internally nucleated muscle cells, consistent with a myopathy phenotype. Interestingly, Col6a3mice are smaller in size, with their fat, muscle, and bone kept proportional compared to wild-type littermates. CONCLUSIONS: In summary, we performed the validation and preliminary phenotypic characterization of a novel Col6a3 knockout mouse model that could be further characterized and used to study COL6A3 biology and model collagen VI-associated diseases.