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Alport syndrome (AS) is an inherited disorder characterized by glomerular basement membrane (GBM) abnormality and development of chronic kidney disease at an early age. The cause of AS is a genetic mutation in type IV collagen, and more than 80% of patients have X-linked AS (XLAS) with mutation in COL4A5. Although the causal gene has been identified, mechanisms of progression have not been elucidated, and no effective treatment has been developed. In this study, we generated a Col4a5mutant mouse harboring a nonsense mutation (R471X) obtained from a patient with XLAS using clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated system. Col4a5mRNA and protein expressions were not observed in the kidneys of hemizygous R471X male mice. R471X mice showed proteinuria and hematuria. Pathology revealed progression of glomerulosclerosis and interstitial fibrosis by age. Electron microscopy identified irregular thickening in GBM accompanied by irregular lamination. These observations were consistent with the clinical and pathological features of patients with AS and other established models. In addition, our mice models develop end-stage renal disease at the median age of 28 weeks, much later compared to previous models much more consistent with clinical course of human XLAS. Our models have advantages for future experiments in regard with treatment for human XLAS.

A mutant strain KF87 of E. coliwith a defective ß‐subunit (Ala‐151 → Val) of F1‐ATPase was isolated. The mutation is within the conserved sequence (G‐X‐X‐X‐X‐G‐K‐T/S) of nucleotide‐binding proteins. The mutant F1‐ATPase had a much higher rate of uni‐site hydrolysis of ATP than the wild type, and about 6% of the wild‐type multi‐site activity. The mutant enzyme showed defective transmission of conformational change(s) between the ligand‐ and aurovertin‐binding sites.

A mutant strain KF87 of E. coliwith a defective ß-subunit (Ala-151 → Val) of F 1-ATPase was isolated. The mutation is within the conserved sequence (G-X-X-X-X-G-K-T/S) of nucleotide-binding proteins. The mutant F 1-ATPase had a much higher rate of uni-site hydrolysis of ATP than the wild type, and about 6% of the wild-type multi-site activity. The mutant enzyme showed defective transmission of conformational change(s) between the ligand- and aurovertin-binding sites.