Mouse Model of X-Linked Alport Syndrome

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DESCRIPTION (provided by applicant): Alport syndrome is the most common genetic disorder of the renal glomerulus, affecting an estimated 1 in 5,000 individuals. Roughly 85% of cases are X-linked, resulting from mutations in the COL4A5 gene, which encodes the c¿(IV) chain of basement membrane type IV collagen. There are currently no effective treatments for Alport syndrome. Males with X-linked disease suffer inexorable progression to end-stage kidney disease. Although female carriers generally have a benign course, an estimated 15% develop chronic renal failure. The premise of this application is that progress towards understanding X-linked Alport syndrome, as grounds for therapy, will be advanced immeasurably by the availability of mouse models. We are generating mouse lines with a Co14a5 point mutation, producing a premature stop, and corresponding to a known human mutation. As X-linked Alport syndrome is an archetypal basement membrane disorder, producing hematuria as a primary manifestation, we plan to build on existing knowledge of the glomerular capillary wall, to investigate the likelihood of its biomechanical failure in our model. Specific Aims are: 1) To complete generation of a transgenic mouse line with a Co14a5 point mutation; 2) To characterize basic structural and functional features of the mutant phenotype; and 3) To initiate comparison of glomerular capillary homeostasis in mutant and control mice.The Principal Investigator is an accomplished molecular biologist and physiologist with primary research interests in Alport syndrome. He joins researchers at the University of Minnesota responsible for historic contributions to this field. Additional collaborators at the University of Minnesota, with expertise in the areas of glomerular physiology and mouse genetics, will contribute to proposed efforts towards strengthening the foundations for effective therapies.