In the 3.5 years since research began under the auspices of this grant, the project laboratory has been successful in using the candidate gene approach to identify pathogenic mutations in five different genes that cause various forms of retinitis pigmentosa (RP) and other human photoreceptor diseases. The project laboratory was the first to report four of the five gene identifications. Despite these successes, well over two-thirds of cases of RP still have an unknown cause. Based on the findings of the project laboratory and other laboratories, it appears that the nonallelic and allelic heterogeneity among patients with RP and allied diseases is enormous, with various mutations at any of perhaps 100 different loci being able to cause clinically relevant disease, including blindness. The project laboratory has a computer-database managed collection of DNA from thousands of patients with a variety of photoreceptor degenerations and dysfunctions. The applicants will enhance the phenotypic diversity of this collection by enrolling additional patients with hereditary retinal degenerations and dysfunctions. The applicants propose to continue to select candidate genes having an important role in the physiology of the photoreceptors or other retinal cells, and to analyze those genes for potential mutations in patients with photoreceptor degeneration or dysfunction. They will apply streamlined techniques for mutation screening to increase the number of unrelated cases surveyed with each selected candidate gene. If successful, this research should identify additional genes causing forms of hereditary blindness such as RP.
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