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

Abstract

Understanding the underlying pathogenesis ofLAMA2-related muscular dystrophy (LAMA2-MD) have been hampered by lack of genuine mouse model. We created a newLama2knockout mouse (dyH/dyH) and reported here its close simulation to human neuropathology and symptoms. We first established thatLama2was 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. OurLama2knockout mice confirmed specific decreasedLama2expression 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 dyH/dyHmice were showed aberrant structure of muscle cytoskeletons which impaired normal muscle development and resulted in weakness. This is the first reported genuine model simulating humanLAMA2-MD. We can use it to study the molecular pathogenesis and develop effective therapies.