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S. Brunner, S. Skosyrski, R. Kirschner-Schwabe, K. Ruether, W. Berger; Retinal Degeneration in a Mouse Model for X-Linked Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2198.
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© ARVO (1962-2015); The Authors (2016-present)
To understand the pathophysiology and molecular mechanisms leading to retinal degeneration in a mouse model carrying an in-frame deletion of exon 4 of the retinitis pigmentosa GTPase regulator gene (RpgrΔEx4).
The RpgrΔEx4 mutation was bred into the C57BL/6 and BALB/c background over several generations. For electroretinography (ERG), mice were measured at five different time points (1, 3, 6, 9 and 12 months) under scotopic and photopic conditions. For morphological characterization, the thickness of the ONL, IS and OS was determined and the density of nuclei in the ONL was counted in an area of 100 um2 on semithin plastic sections. Additionally, immunohistochemical localization of proteins of the phototransduction cascade was performed on wild type and mutant retina in mice of 1 and 12 months of age.
Functional analysis of the BL/6 RpgrΔEx4 mutant mouse line by ERG revealed a decrease of the rod photoreceptor response to light stimuli starting at 3 months of age. This reduction was slightly progressive over the different time points examined. Interestingly, neither there were alterations in the response of the second order neurons (b-wave) nor in the photopic response at any time point. Morphometric analyses of retinal sections showed a slightly decreased thickness of the photoreceptor nuclear layer (ONL) and the inner and outer segments of photoreceptor cells. Rhodopsin and cone opsin were found to be mislocalized in mutant animals already at one month of age. Surprisingly, in the BALB/c line we observed a more severe retinal phenotype primarily involving the cone system.
Overall, both Rpgr mutant mouse lines presented with a retinal degeneration phenotype. In the BL/6 line, the progressive reduction in photoreceptor response to light correlates with the mild changes in retinal morphology. Of note, proteins of the phototransduction cascade showed localization defects before the onset of rod dysfunction indicating that these defects precede the degeneration. In addition, our results further support the role of RPGR in rods as well as in cones. Further studies will focus on the influence of putative genetic modifiers of retinal degeneration.
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