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1 From the Department of Ophthalmology and Visual Sciences, College of Medicine, and the 2 Department of Biological Sciences, College of Liberal Arts and Sciences, University of Illinois at Chicago; the 3 Research Service, Hines VA Hospital, Illinois 4 Departments of Neurology and 5 Ophthalmology, Stritch School of Medicine, Loyola University of Chicago, Maywood, Illinois; the 6 Department of Ophthalmology, New England Eye Center, Boston, Massachusetts; and 7 Saint Louis University Eye Institute and the Cell and Molecular Biology Graduate Program, Saint Louis University School of Medicine, Missouri.
PURPOSE. To characterize the process by which overexpression of normal opsin leads to photoreceptor degeneration.
METHODS. Three transgenic mouse lines were generated that express different levels of an opsin with three amino acid modifications at the C terminus. These modifications created an epitopic site that can be readily distinguished from the endogenous protein using a bovine opsin-specific antibody. Evidence of degeneration associated with opsin overexpression was provided by anatomic studies and electroretinogram (ERG) recordings. Western blot analysis was used to confirm the production of the transgenic opsin, and an enzyme-linked immunosorbent assay (ELISA) was used to determine the amounts of opsin overexpressed in each line. Immunocytochemistry was used to determine the cellular localization of transgenic opsin. Amounts of 11-cis retinal were determined by extraction and high-performance liquid chromatography (HPLC).
RESULTS. Opsin expression levels in the three lines were found to be 123%, 169%, and 222% of the level measured in nontransgenic animals, providing direct correlation between the level of transgene expression and the severity of the degenerative phenotype. In the lower expressing lines, ERG a-wave amplitudes were reduced to less than approximately 30% and 15% of normal values, whereas responses of the highest expressing line were indistinguishable from noise. In the lowest expressor, a 26% elevation in 11-cis retinal was observed, whereas in the medium and the high expressors, 11-cis retinal levels were increased by only 30% to 33%, well below the 69% and 122% increases in opsin levels.
CONCLUSIONS. The overexpression of normal opsin induces photoreceptor degeneration that is similar to that seen in many mouse models of retinitis pigmentosa. This degeneration can be induced by opsin levels that exceed by only approximately 23% that of the normal mouse retina. Opsin overexpression has potential implications in retinitis pigmentosa.
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