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R. G. Schmidt-Kastner, D. Reis, M. Preising, J. Blanks, C. K. Dorey; Localization of the ER-protein Wolframin (Wolfram syndrome 1-WFS1) in the Mouse Retina. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2143.
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© ARVO (1962-2015); The Authors (2016-present)
WFS1/wolframin mutations cause the rare Wolfram syndrome 1 (OMIM 606201), associated with optic nerve atrophy, diabetes mellitus, diabetes insipidus and hearing loss. Wolframin is expressed in the endoplasmic reticulum (ER) whereas optic nerve atrophy is usually associated with mitochondrial failure. Wolframin influences Ca2+ fluxes in ER, interacts with Atp1b1 (Na-K-ATPase), regulates BANK1 (linked to IP3 receptor), and participates in the ER stress response. Previously, we localized wolframin to monkey and human retinal ganglion cells (RGCs) under conditions of delayed fixation. This study localized wolframin in mouse retina after immediate fixation.
Cryostat sections of paraformaldehyde-fixed eyes from C56Bl/6 pigmented and Balb/c albino mice were studied with immunofluorescence using rabbit anti-wolframin antibodies. ARPE-19 cells were seeded on coverslips, fixed and studied using double labeling with anti-wolframin antibodies and DAPI.
Sections through the retina of pigmented and albino mice showed strong labeling of neurons in the ganglion cell layer, cell bodies and processes of Mueller cells, neurons in the inner nuclear layer, and a diffuse line in the position of the inner segments of photoreceptors. Strong cytoplasmic labeling of the RPE was noted in the albino retina. Double labeling confirmed cytoplasmic expression of wolframin in ARPE-19 cells.
Reduction or lack of wolframin in Wolfram syndrome 1 could cause ER dysfunction in RGCs, possibly involving the IP3 receptor 1 and abnormal Ca2+ fluxes. Mutant wolframin is reported to form Ca2+ channels that lack feedback regulation on Ca2+ flux. Resulting high cytoplasmic Ca2+ could sensitize mitochondria and thus explain the phenotype of optic nerve atrophy shared with mitochondrial disease. Since WFS1 polymorphisms have been recently associated with the risk of type 2 diabetes, studies of wolframin in mouse models of diabetes may shed further light on the role of RGCs and RPE in diabetic retinopathy.
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