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Mouse Model of X-Linked Alport Syndrome

Michelle N. Rheault^*, Stefan M. Kren, Beth K. Thielen, Hector A. Mesa, John T. Crosson, William Thomas, Yoshikazu Sado^||, Clifford E. Kashtan^* and Yoav Segal

*Division of Pediatric Nephrology, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota; Division of Renal Diseases and Hypertension, Department of Medicine, University of Minnesota, Minneapolis, Minnesota; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota; Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota; and ^||Shigei Medical Research Institute, Okayama, Japan

Correspondence to Dr. Yoav Segal, MMC 736, 420 Delaware Street SE, Minneapolis, MN 55455. Phone: 612-626-6654; Fax: 612-626-3840; E-mail: ysegal{at}tc.umn.edu

ABSTRACT. X-linked Alport syndrome (XLAS) is a progressive disorder of basement membranes caused by mutations in the COL4A5 gene, encoding the 5 chain of type IV collagen. A mouse model of this disorder was generated by targeting a human nonsense mutation, G5X, to the mouse Col4a5 gene. As predicted for a nonsense mutation, hemizygous mutant male mice are null and heterozygous carrier female mice are mosaic for 5(IV) chain expression. Mutant male mice and carrier female mice are viable through reproductive age and fertile. Mutant male mice died spontaneously at 6 to 34 wk of age, and carrier female mice died at 8 to 45 wk of age, manifesting proteinuria, azotemia, and progressive and manifold histologic abnormalities of the kidney glomerulus and tubulointerstitium. Ultrastructural abnormalities of the glomerular basement membrane, including lamellation and splitting, were characteristic of human XLAS. The mouse model described here recapitulates essential clinical and pathologic findings of human XLAS. With 5(IV) expression reflecting X-inactivation patterns, it will be especially useful in studying determinants of disease variability in the carrier state.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673