X-linked Alport syndrome is a hereditary glomerulonephritis in which progressive loss of kidney function is often accompanied by progressive loss of hearing. Ultrastructural defects in glomerular basement membranes (GBM) of Alport syndrome patients implicate an altered structural protein as the cause of nephritis. The product of COL4A5, the alpha 5(IV) collagen chain, is a specific component of GBM within the kidney, and the gene maps to the same X chromosomal region as does Alport syndrome. Three structural aberrations were found in COL4A5, in intragenic deletion, a Pst I site variant, and an uncharacterized abnormality, which appear to cause nephritis and deafness, with allele-specific severity, in three Alport syndrome kindreds in Utah.

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We have identified and extensively charac-

Alport syndrome is a progressive hereditary kidney disease characterized by hematuria, sensorineural hearing loss and ocular lesions with structural defects in the glomerular basement membrane (GBM). The gene frequency has been estimated to be 1:5000. The disease is primarily X chromosome-linked, but autosomal forms have also been reported. The X-linked form has been shown to be caused by mutations in a recently identified alpha 5(IV) collagen chain gene (COL4A5). We have isolated cDNA clones for providing the entire primary structure of the human alpha 5(IV) chain. The gene has been located to the Xq22 region. Using antibodies against synthetic peptides, the alpha 5(IV) chain was shown to be located in the kidney only in the glomerular basement membrane. Thus far, the exon-intron structure has been determined for a large portion of the gene which probably has a size of over 200 kb. Numerous different mutations have been identified in the COL4A5 gene. The mutations include single base mutations, large deletions and other major rearrangements such as inversion and duplication. The consequences of the mutations observed can be considered sufficient to cause structural and functional defects in the type IV collagen molecule and, therefore, also the GBM network. This, in turn can explain the disruption of the GBM and hematuria occurring in these Alport patients. Alport syndrome is the first genetic basement membrane and kidney disease whose gene has been cloned. These recent results have enabled the development of antibodies and DNA probes for accurate diagnosis of Alport syndrome.