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In conditions of limited chromophore supply rods entrap 11-cis-retinal leading to loss of cone function and cell death

机译：在生色团供应杆有限的情况下，会捕获11-顺-视网膜，导致视锥功能丧失和细胞死亡

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RPE65 is a retinoid isomerase required for the production of 11-cis-retinal, the chromophore of both cone and rod visual pigments. We recently established an R91W knock-in mouse strain as homologous animal model for patients afflicted by this mutation in RPE65. These mice have impaired vision and can only synthesize minute amounts of 11-cis-retinal. Here, we investigated the consequences of this chromophore insufficiency on cone function and pathophysiology. We found that the R91W mutation caused cone opsin mislocalization and progressive geographic cone atrophy. Remnant visual function was mostly mediated by rods. Ablation of rod opsin corrected the localization of cone opsin and improved cone retinal function. Thus, our analyses indicate that under conditions of limited chromophore supply rods and cones compete for 11-cis-retinal that derives from regeneration pathway(s) which are reliant on RPE65. Due to their higher number and the instability of cone opsin, rods are privileged under this condition while cones suffer chromophore deficiency and degenerate. These findings reinforce the notion that in patients any effective gene therapy with RPE65 needs to target the cone-rich macula directly to locally restore the cones' chromophore supply outside the reach of rods
机译：RPE65是类视黄醛异构酶，是产生11-顺-视网膜（视锥和视杆色素的生色团）所必需的。我们最近为受RPE65突变影响的患者建立了R91W敲入小鼠品系作为同源动物模型。这些小鼠的视力受损，只能合成微量的11-顺-视网膜。在这里，我们调查了这种生色团不足对锥体功能和病理生理的影响。我们发现R91W突变引起视锥蛋白定位错误和进行性地理视锥萎缩。残余的视觉功能主要由视杆介导。棒视蛋白的消融纠正了视蛋白视锥细胞的定位并改善了视锥视网膜功能。因此，我们的分析表明，在有限的发色团条件下，供应杆和视锥竞争11-顺-视网膜，其源自依赖于RPE65的再生途径。由于视锥细胞视蛋白的数量较多和不稳定，因此在这种情况下视杆具有优势，而视锥细胞发色团缺乏并退化。这些发现强化了这样的观念，即在患者中，任何有效的RPE65基因治疗都需要直接靶向富含视锥细胞的黄斑，以局部恢复视锥细胞触角之外的视锥细胞生色团供应。

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