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Dorothee Roell, Jutta Schlegel, Christoph Friedburg, Birgit Lorenz, Knut Stieger; Correlation of morphology and function in a mouse model of X-linked retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 2013;54(15):660.
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Retinitis pigmentosa (RP) is a heterogeneous group of hereditary disorders. In humans, over 80% of X-linked retinitis pigmentosa (XLRP) cases are caused by point mutations in the terminal exon ORF15 of the gene encoding the retinitis pigmentosa GTPase regulator (RPGR). This region is therefore called a mutation hot spot. The aim of this study is to correlate morphological and functional data of a mouse model for XLRP due to a point mutation in the ORF15 as a first step towards the development of therapeutic interventions.
Animals were investigated at different time points between 1 to 21 months of age. Morphological analysis was performed using immunohistochemistry with specific antibodies for rhodopsin, S- and LM-opsin on cryosections of the retinae. In addition fundus appearance and vascular structure of the retinae were investigated using fundus photography with additional fundus angiography using the Micron III camera (Phoenix Research Laboratories). To assess function, electroretinography (ERG) examinations were performed under scotopic and photopic conditions using the Espion e 3 desktop system (Diagnosys LLC).
Morphological analysis revealed diffuse, widespread white dots in the fundus of affected animals, appearing from the age of 6 months on. Immunhistochemical analysis showed delocalization of S-opsin as early as 3 months of age, increasing with age. ERG a- and b-wave amplitudes under both dark- and light-adapted conditions were moderately reduced starting at 6 months of age. This reduction continued progressively up to 21 months of age, when a-wave amplitudes were reduced to 20% of normal. Oscillatory potentials were present even at late stage of the disease.
This mouse model with a humanized point mutation in ORF15 of rpgr exhibits morphological alterations like opsin delocalization and fundus changes, and functional alterations in ERG recordings, both starting around the same age. Interestingly, the kinetics of the pathology appear to be milder compared to the human XLRP phenotype. This mouse model will make a substantial contribution to the development of a new therapeutic strategy for further retinal gene therapy trials.
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