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Rachel Stupay, W Clay Smith, Wen-Tao Deng, Ping Zhu, William Hauswirth, Astra Dinculescu; A retinal phenotype in Usher IIIA mouse models. Invest. Ophthalmol. Vis. Sci. 2013;54(15):298.
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© ARVO (1962-2015); The Authors (2016-present)
Mutations in the Clarin-1 (CLN1) gene are the causative factor for Usher Syndrome Type III (USH3A), an autosomal recessive disorder that presents with progressive deafness and retinal degeneration (RD) in humans. Currently, there is no apparent retinal phenotype in the existing USH3A mouse models, with both CLN1 knock-out and the N48K knock-in mutant mice displaying early hearing loss, but normal retinal morphology and function. In this study we attempt to uncover a retinal phenotype by comparing the pattern of light-driven arrestin1 translocation in the above mouse models for USH3A and their isogenic wild-type controls.
Adult CLN1 knock-out, CLN1 N48K knock-in, and control mice were dark adapted overnight, then exposed to light under controlled conditions. Retinal sections were analyzed by immunostaining for arrestin1 and postsynaptic density protein 95 (PSD 95). Quantification of arrestin1 translocation was performed by measuring the staining intensity in retinal cross-sections from WT and Ush3A mice using NIH Image J software.
Arrestin1 distribution in response to light displays a substantial movement towards the outer segments in both wild-type and Ush3A photoreceptors. However, comparison of the pattern of arrestin1 translocation between normal and mutant retinas is different with respect to the retention of arrestin1 in outer plexiform layer (OPL), with uniform and persistent arrestin1 immunostaining remaining within the OPL of mutant USH3A photoreceptors after light exposure. Quantification of arrestin1 staining in the OPL demonstrated that the signal was significantly greater in mutant mice compared to wild-type, suggesting that arrestin1 movement from the OPL was delayed in the Ush3A mice.
These results document a retinal phenotype for Ush3A mice with respect to arrestin1 translocation in response to light. This phenotype will be used to test potential retinal therapies for USH3A, including AAV-mediated delivery of the missing wild-type CLN1 cDNA to the knock-out and N48K knock-in retinas.
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