A novel mouse model for LAMA2-related muscular dystrophy with analysis of molecular pathogenesis and clinical phenotype.

Our understanding of the molecular pathogenesis of LAMA2-related muscular dystrophy (LAMA2-MD) requires improving. Here, we report the phenotype, neuropathology, and transcriptomics data (scRNA-seq and bulk RNA-seq) of a new Lama2 knockout mouse (dy^H/dy^H) which was created based on the human LAMA2-MD mutation hotspot region using CRISPR-Cas9. The dy^H/dy^H mice presented a severe phenotype with muscular dystrophy. Mouse brain scRNA-seq showed that Lama2 gene was expressed predominantly and specifically in vascular and leptomeningeal fibroblasts and vascular smooth muscle cells, and weakly in astrocytes in wild-type mouse. Laminin α2 expression on the cortical surface was observed with immunofluorescence. In dy^H/dy^H, Lama2 expression was decreased in those cell types, which might be associated with the disruption of gliovascular basal lamina assembly. Additionally, transcriptomic investigation of muscles showed 2020 differentially expressed genes, mainly associated with the impaired muscle cytoskeleton and development. In summary, this study provided potentially useful information for understanding the molecular pathogenesis of LAMA2-MD.