Deputy manager Shanghai Model Organisms Center Shanghai, China (People's Republic)
Disclosure(s):
Leon Xu: No relevant disclosure to display
Introduction/Rationale: Alport syndrome (AS) is a rare hereditary kidney disease caused by mutations in the genes encoding the α3, α4, or α5 chains of type IV collagen. Over 80% of AS cases are X-linked (XLAS), resulting from mutations in the COL4A5 gene on the X chromosome, which lead most affected males to develop end-stage renal disease in their 20s and 30s. Given the lack of curative therapies and the limited efficacy of ACE inhibitors, novel AS animal models are essential for developing new treatment strategies.
Methods: Two Col4a5 mutant mouse models carrying nonsense mutations in exon 21 (c. 1411 C > T, p. R471X) or exon 19 (c. 1117 C > T, p. R373X) were established using the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) system, and the corresponding mutations were confirmed by sequencing. Then, the phenotypes were investigated by the measurement of urinary and blood biochemical parameters and histological examination. Finally, Col4a5-R471X mice were employed to evaluate the efficacy of ACEi (ramipril) monotherapy.
Results: Phenotypic analysis revealed that both Col4a5-R471X and Col4a5-R373X mice developed AS-like pathology, characterized by elevated urinary albumin, albumin-to-creatinine ratio, serum urea, creatinine and total protein levels. Histological examination further showed glomerular abnormalities in mutant mice, indicating impaired renal function that closely resembled the clinical manifestations. Moreover, treatment with ACEi effectively ameliorated renal dysfunction, inflammation, and fibrosis throughout the progression of XLAS in Col4a5-R471X mice.
Conclusion: In conclusion, these COL4A5 mutant mouse models offer an valuable preclinical platform for investigating AS pathogenesis and developing new therapeutic interventions.
