ALPORT SYNDROME GENETICS AND MUTATION DETECTION

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DESCRIPTION: Defects in the COL4A5 gene, which encodes the distinct basement membrane collagen alpha5(V), have recently been demonstrated in Alport Syndrome (AS), a hereditary progressive glomerulonephritis. The disease shows substantial phenotypic variation, similar to osteogenesis imperfecta, where various defects in COL1A1 and COL1A2 cause bone fragility with a very wide range of phenotypic severity. In AS, the disease varies with respect to the severity of associated deafness, the age of onset and end-stage renal disease (which requires kidney transplant or permanent dialysis therapy), and the presence of characteristic eye and blood abnormalities. The variability of hearing loss appears to be due to allelic variation at COL4A5, since two mutations which lie entirely within the gene cause deafness of different severities. The applicants propose to perform genetic studies to determine if the genetic defect in any Alport family is at a locus other than COL4A5. As part of a collaborative effort, the applicants will examine the COL4A5 gene for mutation in families where the defect appears to reside at this locus. Comprehensive clinical characterization of these families by collaborators will be conducted and together these studies will form the basis for a correlation of the molecular defects with the variable phenotypes. Establishing this correlation will improve the efficacy of therapeutic intervention in the disease and lead to a better understanding of the role of COL4A5 in the molecular architecture of the basement membrane, perhaps suggesting some means of intervening in the progressive disease process. The circumstances of the origin of new COL4A5 mutations will also be examined to determine if there are any important risk factors.