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      Animal Models of Alport Syndrome: Advancing the Prospects for Effective Human Gene Therapy


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          Several animal models for Alport syndrome have been described. These are available for studies on the pathogenetic mechanisms of the disease, as well as for the development of new technologies for gene therapy in this progressive hereditary kidney disease. This review summarizes current knowledge on the molecular basis of Alport syndrome, and on the animal models which all remarkably well resemble the human disease. Recent work aimed at the development of gene therapy, including hurdles and progress are discussed.

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          Identification of mutations in the alpha 3(IV) and alpha 4(IV) collagen genes in autosomal recessive Alport syndrome.

          Alport syndrome (AS) is an hereditary disease of basement membranes characterized by progressive renal failure and deafness. Changes in the glomerular basement membrane (GBM) in AS suggest that the type IV collagen matrix, the major structural component of GBM, is disrupted. We recently isolated the genes for two type IV collagens, alpha 3(IV) and alpha 4(IV), that are encoded head-to-head on human chromosome 2. These chains are abundant in normal GBM but are sometimes absent in AS. We screened for mutations in families in which consanguinity suggested autosomal recessive inheritance. Homozygous mutations were found in alpha 3(IV) in two families and in alpha 4(IV) in two others, demonstrating that these chains are important in the structural integrity of the GBM and that there is an autosomal form of AS in addition to the previously-defined X-linked form.
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            Collagen IV alpha 3, alpha 4, and alpha 5 chains in rodent basal laminae: sequence, distribution, association with laminins, and developmental switches

            Collagen IV is a major component of vertebrate basal laminae (BLs). Studies in humans have revealed a family of genes encoding alpha 1- alpha 6 collagen IV chains and implicated alpha 3-alpha 6 in disease processes (Goodpasture and Alport syndromes and diffuse leiomyomatosis). To extend studies of these components to an experimentally accessible animal, we cloned cDNAs encoding partial collagen alpha 3, alpha 4, and alpha 5(IV) chains from the mouse. Ribonuclease protection assays showed that all three genes were expressed at highest levels in kidney and lung; alpha 5(IV) was also expressed at high levels in heart. We then made antibodies specific for each collagen IV chain. Immunohistochemical studies of several tissues revealed many combinations of collagen IV chains; however, alpha 3 and alpha 4 (IV) were always coexpressed, and only appeared in BLs that were alpha 5(IV) positive. The alpha 3-alpha 5(IV) chains were frequently but not exclusively associated with the S (beta 2) chain of laminin, as were the alpha 1, 2 (IV) collagen chains with laminin B1 (beta 1). An analysis of developing rat kidney BLs showed that newly formed (S-shaped) nephrons harbored collagen alpha 1 and alpha 2(IV) and laminin B1; maturing (capillary loop stage) BLs contained collagen alpha 1-alpha 5(IV) and laminin B1 and S-laminin; and mature glomerular BLs contained mainly collagen alpha 3-alpha 5(IV) and S-laminin. Thus, collagen alpha 1 and alpha 2(IV) and laminin B1 appear to be fetal components of the glomerular BL, and there is a developmental switch to collagen alpha 3-alpha 5(IV) and S-laminin expression.
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              Glomerular Basement Membrane


                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                February 2000
                14 January 2000
                : 8
                : 1
                : 1-7
                aDivision of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden, and bDepartment of Pediatric Laboratory Medicine, Hospital for Sick Children, University of Toronto, Ont., Canada
                20641 Exp Nephrol 2000;8:1–7
                © 2000 S. Karger AG, Basel

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                Page count
                Tables: 1, References: 38, Pages: 7
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/20641
                Self URI (text/html): https://www.karger.com/Article/FullText/20641
                Self URI (journal page): https://www.karger.com/SubjectArea/Nephrology

                Cardiovascular Medicine,Nephrology
                Type-IV collagen,Gene therapy,Kidney,Alport syndrome,Animal models
                Cardiovascular Medicine, Nephrology
                Type-IV collagen, Gene therapy, Kidney, Alport syndrome, Animal models


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