Disruption of the 11-cis-retinol dehydrogenase gene leads to accumulation of cis-retinols and cis-retinyl esters

To elucidate the possible role of 11-cis-retinol dehydrogenase in the visua l cycle and/or 9-cis-retinoic acid biosynthesis, we generated mice carrying a targeted disruption of the 11-cis-retinol dehydrogenase gene. Homozygous 11-cis-retinol dehydrogenase mutants developed normally, including their r etinas. There was no appreciable loss of photoreceptors. Recently, mutation s in the 11-cis-retinol dehydrogenase gene in humans have been associated w ith fundus albipunctatus. In 11-cis-retinol dehydrogenase knockout mice, th e appearance of the fundus was normal and punctata typical of this human he reditary ocular disease were not present. A second typical symptom associat ed with this disease is delayed dark adaptation. Homozygous 11-cis-retinol dehydro genase mutants showed normal rod and cone responses. 11-cis-Retinol dehydrogenase knockout mice were capable of dark adaptation. At bleaching levels under which patients suffering from fundus albipunctatus could be de tected unequivocally, 11-cis-retinol dehydrogenase knockout animals display ed normal dark adaptation kinetics, However, at high bleaching levels, dela yed dark adaptation in 11-cis-retinol dehydrogenase knockout mice was notic ed. Reduced 11-cis-retinol oxidation capacity resulted in 11-cis-retinol/13 -cis-retinol and 11-cis-retinyl/13-cis-retinyl ester accumulation. Compared with wild-type mice, a large increase in the 11-cis-retinyl ester concentr ation was noticed in 11-cis-retinol dehydrogenase knockout mice. In the mur ine retinal pigment epithelium, there has to be an additional mechanism for the biosynthesis of 11-cis-retinal which partially compensates for the los s of the 11-cis-retinol dehydrogenase activity. 11-cis-Retinyl ester format ion is an important part of this adaptation profess. Functional consequence s of the loss of 11-cis-retinol dehydrogenase activity illustrate important differences in the compensation mechanisms between mice and humans. We fur thermore demonstrate that upon 11-cis-retinol accumulation, the 13-cis-reti nol concentration also increases. This retinoid is inapplicable to the visu al processes, and we therefore speculate that it could be an important cata bolic metabolite and its biosynthesis could be part of a process involved i n regulating 11-cis-retinol concentrations within the retinal pigment epith elium of 11-cis-retinol dehydrogenase knockout mice.