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J. D. Chrispell, K. L. Feathers, I. Kurth, A. Gal, C. Hübner, D. A. Thompson; Retinoid Dehydrogenase/Reductase Activity and Expression in Rdh12 Knockout Mice. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3526. doi: https://doi.org/.
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RDH12 loss-of-function mutations are associated with severe and early-onset autosomal recessive retinal degeneration, resulting in profound retinal pathology and visual handicap in patients. However, the unique role of RDH12 in retinal physiology is not yet understood. To better define the function of RDH12 within the network of multiple short chain dehydrogenases/reductases (RDHs) expressed in the retina, we are studying the phenotype of Rdh12-deficient mice.
Rdh12 knockout mice were generated as described previously (Mol Cell Biol. 2007;27:1370-9). Eye retinoid content, and product formation from retinoid reductase activity in retina homogenates in the presence of exogenous substrates and NADPH, were assayed using normal phase HPLC. Expression was assayed using qRT-PCR, western, and immunohistochemical analysis. Retinal thickness was evaluated using morphometric analysis.
Retinal degeneration was not observed in Rdh12-deficient mice at up to 21 months-of-age. The retinoid content of Rdh12-deficient and wild type mice was similar under light- and dark-adapted conditions, and following recovery from bleaching. However, in vitro assays of the reduction of excess all-trans retinal and 11-cis retinal in retina homogenates showed significantly decreased activity in knockout compared to wild type animals. Expression of Rdh12 co-localized with Rdh11 and Dhrs3(retSDR1) present at relatively high levels in photoreceptor inner segments in human and mouse, but did not coincide with RDH8(prRDH) in photoreceptor outer segments.
Rdh12-deficiency in mouse does not restrict visual cycle function by limiting 11-cis retinal synthesis in vivo, but does decrease the capacity of the retina to reduce all-trans retinal and 11-cis retinal in vitro. In the absence of Rdh12 in mouse, RDH activity provided by other isoforms, potentially expressed in the inner segment, is sufficient to maintain wild type levels of oxidized and reduced retinoids in vivo. In the human retina, differences in the expression or catalytic activity of these RDH isoforms may result in incomplete compensation of RDH12-deficiency, with attendant pathology stemming, directly or indirectly, from increases of all-trans retinal and other short chain aldehydes.
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