Mouse model of X-linked Alport syndrome with K229X mutation in the COL4A5 gene

X-linked Alport syndrome (XLAS) is a hereditary glomerular basement membrane (GBM) disease caused by COL4A5 mutations, leading to end-stage renal disease. With unclear pathogenesis and limited treatments, reliable animal models are urgently needed. In this study, the mutation K229X in COL4A5 detected in XLAS patients was introduced into mice model by CRISPR/Cas. The clinical manifestations and pathological changes in the K229X mice were characterized through urinary and serum tests, histopathology, immunofluorescence, and transmission electron microscopy. In K229X male mice, we observed significant hematuria and proteinuria, along with azotemia, and noted a marked decrease in the expression of COL4A5 at both the mRNA and protein levels within the kidneys. Pathological examination revealed glomerulosclerosis, increased mononuclear cells in the renal interstitium, interstitial fibrosis, and absence of α5 collagen IV, with histological abnormalities in the glomeruli, renal tubules, and interstitium progressing with age. Electron microscopy found irregular thickening of the GBM, accompanied by irregular layering. The phenotypic and pathological features of this mouse model are consistent with those observed in XLAS patients and other previously established mouse models. This K229X mouse model is of significant importance for exploring the pathogenic mechanisms of XLAS and researching potential therapeutic approaches.