This project aims at producing a genetic model in the pig for investigating the mechanisms by which mutations of the rhodopsin gene lead to photoreceptor death and widespread retinal degeneration in humans. Retinitis pigmentosa (RP) is a heterogeneous group of degenerative disorders that primarily affect photoreceptors and the retinal pigment epithelium. However, the clinical course of the different forms of RP follows a similar well-defined pattern. It is known that these disorders may be caused by mutations at various loci within the genome involving separate genes. Accordingly, the different hereditary types of RP are not produced by an identical defect but the similar end results imply that they share some common steps in pathogenesis. More than twenty point mutations of the rhodopsin gene have been identified in patients with autosomal dominant RP. However, the relationship between these mutations and the mechanisms of RP is not known. Specifically, through what mechanisms do mutations in the rhodopsin gene, which is a rod-specific gene, cause widespread photoreceptor degeneration, including the cones? Although mutations of the rhodopsin gene cannot account for all the known hereditary types of RP, they offer a prototype for studying the pathogenesis of RP. Preliminary experiments on transgenic mice have indicated that a mutant rhodopsin 'transgene' causes photoreceptor dysfunction. If similar transgenic pigs can be generated, it will provide a better model for studying the disease process of RP because the pig eye resembles the human eye much more closely than the mouse does. Whereas the RP disease process in mice is expected not to parallel closely that of the human, it should be very similar in the pig. If transgenic pigs develop RP, they will be useful for studying the pathogenesis as well as possible treatments of RP.
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