Alport syndrome is a disease of the basement membrane that results in a progressive glomerulonephritis often associated with sensorineural hearing loss and defects in the lens of the eye (anterior lenticonis). The more prevalent type has an X-linked mode of inheritance and is due to mutations in the collagen 4A5 gene. A less prevalent form is autosomal and due to mutations in either the collagen 4A3 or 4A4 genes. For the more extensively studied X-linked form, radical mutations are associated with early onset glomerulonephritis with sensorineural hearing loss and anterior lenticonis, while more subtle mutations are associated with a delayed onset glomerulonephritis (early adulthood) with variable expression of the auditory and visual manifestations. Recent studies in the kidneys of rats and mice indicate differential developmental regulation of classical and novel collagen chains. Studies performed in this laboratory (see Preliminary Results) show a parallel phenomenon in the cochlea of mice. These data suggest that the delayed onset in Alport syndrome might be due to a gradual depletion of basement membrane collagen in those tissues that express the novel chains.
The specific aims of the previous cycle of this proposal were directed at using gene targeting in embryo-derived stem cells to produce a murine model for X-linked Alport syndrome. While there-have been problems in producing an X-linked Alport mouse model, a model for autosomal Alport syndrome (a 4A3 gene knockout) is near completion.
Work aim ed at producing the X-linked model will be continued, since this is the most prevalent form of the disease in man. These studies will focus on otopathology in both mouse models. Auditory brainstem response (ABR) will be used to determine the existence of hearing loss and its temporal progression in the animal model. Timepoints before, during, and after the onset will be pinpointed for harvest of cochlear tissue. Postnatal cochlear development in normal and diseased mice will be analyzed by general histology and immunohistology. Expression of the type IV collagen chains and the major basement membrane associated proteins (fibronectin, laminin, heparan sulfate proteoglycan, and entactin) will be examined. Detailed analysis of the cochlea using general histology, immunohistology, and electron microscopic analysis will provide the first look into the molecular nature of Alport disease pathology in this organ. If the molecular and structural defects can be pinpointed, human temporal bones from deceased Alport patients will be examined to determine whether the same defects are present in man.

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