Driessen C A, Winkens H J, Hoffmann K, Kuhlmann L D, Janssen B P, Van Vugt A H, Van Hooser J P, Wieringa B E, Deutman A F, Palczewski K, Ruether K, Janssen J J
Department of Ophthalmology, University of Nijmegen, The Netherlands.
Mol Cell Biol. 2000 Jun;20(12):4275-87. doi: 10.1128/MCB.20.12.4275-4287.2000.
To elucidate the possible role of 11-cis-retinol dehydrogenase in the visual 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 retinas. There was no appreciable loss of photoreceptors. Recently, mutations in the 11-cis-retinol dehydrogenase gene in humans have been associated with fundus albipunctatus. In 11-cis-retinol dehydrogenase knockout mice, the appearance of the fundus was normal and punctata typical of this human hereditary ocular disease were not present. A second typical symptom associated with this disease is delayed dark adaptation. Homozygous 11-cis-retinol dehydrogenase 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 detected unequivocally, 11-cis-retinol dehydrogenase knockout animals displayed normal dark adaptation kinetics. However, at high bleaching levels, delayed dark adaptation in 11-cis-retinol dehydrogenase knockout mice was noticed. 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 concentration was noticed in 11-cis-retinol dehydrogenase knockout mice. In the murine retinal pigment epithelium, there has to be an additional mechanism for the biosynthesis of 11-cis-retinal which partially compensates for the loss of the 11-cis-retinol dehydrogenase activity. 11-cis-Retinyl ester formation is an important part of this adaptation process. Functional consequences of the loss of 11-cis-retinol dehydrogenase activity illustrate important differences in the compensation mechanisms between mice and humans. We furthermore demonstrate that upon 11-cis-retinol accumulation, the 13-cis-retinol concentration also increases. This retinoid is inapplicable to the visual processes, and we therefore speculate that it could be an important catabolic metabolite and its biosynthesis could be part of a process involved in regulating 11-cis-retinol concentrations within the retinal pigment epithelium of 11-cis-retinol dehydrogenase knockout mice.
为阐明11-顺式视黄醇脱氢酶在视觉循环和/或9-顺式视黄酸生物合成中的可能作用，我们构建了携带11-顺式视黄醇脱氢酶基因靶向缺失的小鼠。纯合的11-顺式视黄醇脱氢酶突变体发育正常，包括其视网膜。光感受器没有明显损失。最近，人类11-顺式视黄醇脱氢酶基因的突变与白点状眼底相关。在11-顺式视黄醇脱氢酶基因敲除小鼠中，眼底外观正常，不存在这种人类遗传性眼病典型的点状表现。与这种疾病相关的第二个典型症状是暗适应延迟。纯合的11-顺式视黄醇脱氢酶突变体显示出正常的视杆和视锥反应。11-顺式视黄醇脱氢酶基因敲除小鼠能够进行暗适应。在能够明确检测出白点状眼底患者的漂白水平下，11-顺式视黄醇脱氢酶基因敲除动物表现出正常的暗适应动力学。然而，在高漂白水平下，注意到11-顺式视黄醇脱氢酶基因敲除小鼠存在暗适应延迟。11-顺式视黄醇氧化能力降低导致11-顺式视黄醇/13-顺式视黄醇和11-顺式视黄酯/13-顺式视黄酯积累。与野生型小鼠相比，11-顺式视黄醇脱氢酶基因敲除小鼠中11-顺式视黄酯浓度大幅增加。在小鼠视网膜色素上皮中，必定存在另一种11-顺式视黄醛生物合成机制，该机制可部分补偿11-顺式视黄醇脱氢酶活性的丧失。11-顺式视黄酯的形成是这一适应过程的重要组成部分。11-顺式视黄醇脱氢酶活性丧失的功能后果说明了小鼠和人类在补偿机制上的重要差异。我们还证明，在11-顺式视黄醇积累时，13-顺式视黄醇浓度也会增加。这种类视黄醇不适用于视觉过程，因此我们推测它可能是一种重要的分解代谢产物，其生物合成可能是参与调节11-顺式视黄醇脱氢酶基因敲除小鼠视网膜色素上皮内11-顺式视黄醇浓度过程的一部分。
