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T J Hollingsworth, Alecia Gross; Rhodopsin ADRP Mutant Ter349Glu Causes Retinal Inflammation and Early-Onset Degeneration. Invest. Ophthalmol. Vis. Sci. 2013;54(15):696.
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The Ter349Glu rhodopsin mutant causes a severe retinal phenotype characterized by early-onset and rapid degeneration. Prior in vitro assays showed that Ter349Glu rhodopsin is able to fold and function similarly to wild type (WT) while mislocalizing in polarized cells. To determine the origin of the severe phenotype, we examined the retina of a knock-in mouse bearing the mutation for receptor localization, rod cell morphogenesis and degeneration, and inflammation.
Retinas from Ter349Glu heterozygote and homozygote albino mice were examined for receptor localization, photoreceptor degeneration, and inflammation using fluorescent immunohistochemistry, and the in vivo retinal condition using funduscopy and optical coherence tomography (OCT).
Rods of the Ter349Glu homozygote mice degenerate rapidly and lack a clear delineation between inner and outer segments. In heterozygote animals, the degeneration seen is slowed with approximately two nuclei lost in the outer nuclear layer. In these rods, mislocalization of both WT and the mutant receptor was observed. Labeling for both phospho-STAT3 and F4/80 antigen, each a marker of retinal inflammation, show activation of both the JAK/STAT pathway and macrophages, respectively. Funduscopy reveals hallmarks of retinitis pigmentosa including attenuated retinal vessels and patches of light reflection indicating a loss of neural retina. Examination by OCT reveals detachments between the photoreceptors and the pigmented epithelium.
The rapid degeneration and RP phenotypes observed in homozygote animals are consistent with what is seen in human patients. The lack of obvious rod outer segments is indicative of a loss of proper morphogenesis, possibly due to the occlusion of the C-terminal sorting motif. Mislocalization of the photoreceptor protein could be due to aggregate formation and/or endoplasmic reticulum retention of both the mutant and WT proteins. The presence of activated macrophages in the retinas of homozygote knock-in animals indicates an inflammatory response possibly associated with an infiltration of blood-borne macrophages from the choroid. The activation of the JAK/STAT pathway is indicative of retinal inflammation and may be responsible for lowering the expression levels of rhodopsin through cytokine signaling, possibly in an interleukin-6 dependent manner.
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