Alport syndrome (AS) is a relatively common cause of progressive renal failure and deafness in childhood. AS is predominantly an X-linked disorder affecting males but autosomal forms also exist. The principal investigator and her collaborators have previously shown that mutations in the alpha5(IV) chain of type IV collagen, a structural component of basement membrane, are responsible for a significant fraction of AS cases. The principal investigator has also recently identified a gene encoding an unexpected sixth type IV collagen, alpha6(IV), and shown, in preliminary studies, that the gene is arranged in a head-to-head fashion with the alpha5(IV) gene such that they share a common promoter region. The alpha6(IV) gene is expressed in kidney and is a candidate for As mutations. Indeed the alpha6(IV) gene may account for the mutations in the 40-60% of AS patients in whom alpha5(IV) mutations have been found. In preliminary studies the author has demonstrated the first AS mutation in alpha6(IV) and shown that deletions of the 5' end of the gene lead to AS-associated diffuse esophageal and genital smooth muscle tumors. In the proposed study, the alpha5(IV) and alpha6(IV) gene will be screened for mutations in a wide range of patients with AS to establish the mutations range and genotype/phenotype correlations. Despite the fact that the molecular pathology of the alpha5(IV) and alpha6(IV) chains is being characterized rapidly, the pathogenesis of renal failure in AS remains an enigma. In order to plan logical inventions to retard or halt the disease and to plan a strategy for genetic therapy it is necessary to understand the tissue distribution of these chains, the interactions between the different type IV collagen isoforms, and the regulation of the genes. This proposal addresses these issues by means of biochemical analyses of glomerular basement membrane, studies of transcriptional regulation in vitro and in transgenic mice and immunochemical analyses of a range of tissues. Characterization of the mutations that lead to AS and correlation of these mutations with the various phenotype features of the disease will provide valuable insights into the pathophysiology of the glomerular basement membrane. The study of the alpha6(IV) gene will also lead to the development of methods of screen for mutations in presymptomatic and prenatal at-risk individuals. In the longer term, an understanding of the molecular pathology of the disease may lead to opportunities for delaying the progress of the disease and, ultimately, may suggest methods for genetic therapy.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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General Medicine B Study Section (GMB)
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Brigham and Women's Hospital
United States
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