Fatty acid transport protein 4 (FATP4), a transmembrane protein in the endoplasmic reticulum (ER), is a recently identified negative regulator of the ER-associated retinal pigment epithelium (RPE)65 isomerase necessary for recycling 11-cis-retinal, the light-sensitive chromophore of both rod and cone opsin visual pigments. The role of FATP4 in the disease progression of retinal dystrophies associated with RPE65 mutations is completely unknown. Here we show that FATP4-deficiency in the RPE results in 2.8-fold and 1.7-fold increase of 11-cis- and 9-cis-retinals, respectively, improving dark-adaptation rates as well as survival and function of rods in the Rpe65 R91W knockin (KI) mouse model of Leber congenital amaurosis (LCA). Degradation of S-opsin in the proteasomes, but not in the lysosomes, was remarkably reduced in the KI mouse retinas lacking FATP4. FATP4-deficiency also significantly rescued S-opsin trafficking and M-opsin solubility in the KI retinas. The number of S-cones in the inferior retinas of 4- or 6-mo-old KI;Fatp4^−/− mice was 7.6- or 13.5-fold greater than those in age-matched KI mice. Degeneration rates of S- and M-cones are negatively correlated with expression levels of FATP4 in the RPE of the KI, KI;Fatp4^+/−, and KI;Fatp4^−/− mice. Moreover, the visual function of S- and M-cones is markedly preserved in the KI;Fatp4^−/− mice, displaying an inverse correlation with the FATP4 expression levels in the RPE of the three mutant lines. These findings establish FATP4 as a promising therapeutic target to improve the visual cycle, as well as survival and function of cones and rods in patients with RPE65 mutations.

脂肪酸转运蛋白4（FATP4），内质网（ER）的跨膜蛋白，是内质网相关的视网膜色素上皮细胞的最近鉴定的负调节物（RPE）65异构酶必要回收11-顺式视黄醛，光视锥色素和视锥蛋白视觉敏感的发色团。FATP4在与RPE65突变相关的视网膜营养不良的疾病进展中的作用是完全未知的。在这里，我们显示RPE中的FATP4缺乏导致11-顺式和9-顺式增加2.8倍和1.7倍-视网膜分别改善了Leber先天性黑体病（LCA）的Rpe65 R91W敲入（KI）小鼠模型的暗适应率以及杆的存活和功能。在缺乏FATP4的KI小鼠视网膜中，蛋白酶体中S-视蛋白的降解显着降低，而溶酶体中S-视蛋白的降解却没有明显降低。FATP4缺乏症还大大挽救了S-视蛋白运输和M-视蛋白在KI视网膜中的溶解性。4或6个月大KI下视网膜中S锥体的数量；Fatp4 ^-//小鼠比年龄匹配的KI小鼠高7.6或13.5倍。S-和M-锥的退化率与KI的RPE中FATP4的表达水平负相关；Fatp4 ^+/-和KI; Fatp4 ^-/-老鼠。此外，KI显着保留了S和M锥的视觉功能。Fatp4 ^-/-小鼠，与三个突变株的RPE中的FATP4表达水平呈负相关。这些发现将FATP4确立为改善RPE65突变患者视力循环以及视锥细胞和视杆的存活和功能的有希望的治疗靶标。