Construction and liver phenotypic analysis of mouse models with W483X mutation of Ldlr gene. Construction and liver phenotypic analysis of mouse models with W483X mutation of Ldlr gene

Low density lipoprotein receptor (Ldlr) mutations are one of the main causes of familial hypercholesterolemia (FH), which can induce atherosclerosis and carries a higher lifetime risk of cardiovascular disease, and the W483X mutation of Ldlr is considered the most common newly identified pathogenic mutation in Chinese FH. The clustered regularly spaced short palindromic repeat (CRISPR)/Cas9 system has become an effective tool for gene editing to correct genetic mutations and thereby ameliorate disease. In this study, we confirmed that the highly pathogenic W483X mutation of Ldlr gene found in FH patients could be expressed in hepatocytes in vitro, successfully constructed mouse hepatocyte model, and confirmed that the mutation point mutation of W483X could be expressed in cells. A mouse model with W483X mutation of Ldlr gene was constructed by microinjection using CRISPR/Cas9 gene editing system to investigate the effect of W483X mutations on plasma lipid metabolism and atherosclerosis. Our results showed that the model was successfully constructed, and it could stably survive and breed the next generation, and showed phenotypic differences from previous commonly used mouse models of atherosclerosis, which could share a greater degree of similarity with human atherogenesis, and could be serve as a valuable tool to explore different strategies for treating homozygotes of FH (HoFH) pathogenesis in humans. In conclusion, our findings suggest that the W483X mutation of Ldlr gene can provide experimental strategies for studying cardiovascular injury and its regulatory mechanism from the perspective of development.