Abstract Understanding the underlying pathogenesis of LAMA2 -related muscular dystrophy ( LAMA2 -MD) have been hampered by lack of genuine mouse model. We created a new Lama2 knockout mouse (dy H /dy H ) and reported here its close simulation to human neuropathology and symptoms. We first established that Lama2 was predominantly expressed within the cortical surface of normal mouse brain, specifically, highly concentrated in vascular and leptomeningeal fibroblasts and vascular smooth muscle cells with a modest presence within astrocytes. Our Lama2 knockout mice confirmed specific decreased Lama2 expression in those cell types and resulted in disruption of gliovascular basal lamina assembly. This molecular pathogenesis mechanism was elucidated by a novel scRNA-seq. Furthermore, through transcriptomic investigation, these dy H /dy H mice were showed aberrant structure of muscle cytoskeletons which impaired normal muscle development and resulted in weakness. This is the first reported genuine model simulating human LAMA2 -MD. We can use it to study the molecular pathogenesis and develop effective therapies.

A Novel Mouse Model forLAMA2-Related Muscular Dystrophy: Analysis of Molecular Pathogenesis and Clinical Phenotype