1. ¹Department of Genetics, Boys Town National Research Hospital, Omaha, Nebraska, USA
2. ²Center for Matrix Biology, Department of Medicine, Harvard Medical School, Harvard-MIT, Boston, Massachusetts, USA
3. ³Division of Nephrology, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Harvard-MIT, Boston, Massachusetts, USA
4. ⁴Division of Health Sciences and Technology, Division of Nephrology, Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA
5. ⁵Renal Division, Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri, USA
6. ⁶Division of Renal Diseases and Hypertension, Department of Medicine, University of Minnesota and Minneapolis VA Medical Center, Minneapolis, Minnesota, USA
7. ⁷Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

Correspondence: D Cosgrove, Department of Genetics, Boys Town National Research Hospital, 555 No. 30th St, Omaha, Nebraska 68131, USA. E-mail: Cosgrove@boystown.org

Received 11 October 2006; Revised 4 December 2006; Accepted 5 December 2006; Published online 7 February 2007.

Abstract

Alport syndrome, caused by mutations that interfere with the normal assembly of the 345(IV) collagen network in the glomerular basement membrane (GBM), is the most common inherited glomerular disease leading to renal failure. A detailed knowledge of the underlying pathogenic mechanisms is necessary for developing new, more specific, and effective therapeutic strategies aimed at delaying the onset and slowing disease progression. Studies of several dog and mouse models of Alport syndrome have significantly enhanced our understanding of the disease mechanisms and provided systems for testing potential therapies. In the most widely used Col4a3-/- mouse models of autosomal-recessive Alport syndrome (ARAS), the genetic background strongly affects renal survival. One contributing factor may be the strong ectopic deposition of 56(IV) collagen in the GBM of Col4a3-/- mice on the C57BL/6J background, which is almost undetectable on the 129/Sv background. This isoform 'switch' has not been observed in human ARAS, although it had been reported in the dog model of ARAS. In human patients as well as dog and mouse models of X-linked Alport syndrome, the 3–6(IV) collagen chains are absent from the GBM. These biochemical differences among Alport animal models provide an opportunity to determine how the molecular makeup of the GBM affects the glomerular function. At the same time, potentially confounding influences of characteristics unique to a particular strain or model should be carefully considered in the design of studies aiming to define key events underlying the pathobiology of Alport glomerular disease.