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Henry Tseng, Thorfin Riday, Howard Bomze, Ian Barak, Carrie Marean-Reardon, Ben Philpot, Michael Ehlers; Visual impairment in mice expressing glaucoma-associated E50K mutant optineurin. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6176.
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Glaucoma is a leading cause of irreversible blindness that results from degeneration of retinal ganglion cells (RGCs). Primary open angle glaucoma (POAG) is the predominant form of glaucoma in which the intraocular pressure can be high or normal. A major hurdle in studying RGC neurodegeneration in normal pressure POAG is the lack of robust animal disease models. Here, we report a novel mouse model based on the disease-associated E50K mutation in the human OPTN gene. This transgenic mouse recapitulates key clinical characteristics of normal pressure POAG.
Mice with high over-expression of the E50K mutant optineurin have been reported, but resulted in diffuse loss of photoreceptors which is not observed in clinical glaucoma. In contrast, we generated bacterial artificial chromosome (BAC) transgenic mice with low overexpression of the E50K human optineurin (hOPTN) that is closer to normal physiological level. These mice were aged for at least 1.5 years. Gross ocular anatomy, intraocular pressure, retinal histology, and normal central targeting of RGC axons in the brain were assessed. Finally, visual function was assessed by measuring visually-evoked potentials (VEPs) in the primary visual cortex.
These E50K optineurin BAC transgenic mice exhibit normal ocular anatomy, intraocular pressure, and normal RGC axonal projections in the brain as seen in patients. Despite ~30% loss of RGCs, the remainder of the retina appears normal histologically. Functionally, via VEP electrophysiological assessment, these mice exhibit a significant reduction in contrast detection, but not visual acuity or motion detection.
As in human disease, mild overexpression of E50K hOPTN in our BAC transgenic mice resulted in selective loss of RGCs and functional visual impairment. These transgenic mice provide a novel disease model for normal-pressure POAG that may provide mechanistic insights into the RGC degeneration associated with this poorly understood disease, as well as providing a platform to test novel therapeutics.
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