Visual cycle proteins: Structure, function, and roles in human retinal disease

Abstract

Here, we seek to summarize the current understanding of the biochemical and molecular events mediated by visual cycle molecules in the eye. The structures and functions of selected visual cycle proteins and their roles in human retinal diseases are also highlighted. Genetic mutations and malfunctions of these proteins provide etiological evidence that many ocular diseases arise from anomalies of retinoid (vitamin A) metabolism and related visual processes. Genetic retinal disorders such as retinitis pigmentosa, Leber congenital amaurosis, and Stargardt's disease are linked to structural changes in visual cycle proteins. Moreover, recent reports suggest that visual cycle proteins may also play a role in the development of diabetic retinopathy. Basic science has laid the groundwork for finding a cure for many of these blindness-causing afflictions, but much work remains. Some translational research projects have advanced to the clinical trial stage, while many others are still in progress, and more are at the ideas stage and remain yet to be tested. Some examples of these studies are discussed. Recent and future progress in our understanding of the visual cycle will inform intervention strategies to preserve human vision and prevent blindness.

Is Dietary Vitamin A Associated with Myopia from Adolescence to Young Adulthood?

“… 43 – 45 RP is the most common genetically inherited ocular disease and is associated with over 50 different genes. 46 We have identified three genes common to RP and vitamin A. RDH5 and RGR are associated with RP, retinoic acid metabolism, and myopia. RPE65 is common to RP and vitamin A deficiency.…”

A Comparison of the Primary Sensory Neurons Used in Olfaction and Vision

“…Some steps of the visual cycle occur in PR OS but the key step of isomerizing the bond at the 11th carbon of retinal from the trans to cis confirmation is carried out by an isomerase found in the adjacent RPE cells. Interestingly, there is a secondary visual cycle thought to primarily serve cones where the key isomerase is found in the other major support cell for PR, the Muller Glia (Tsin et al, 2018).…”

Pathways and disease-causing alterations in visual chromophore production for vertebrate vision

“…Functional insights often lag significantly behind initial retinal disease genetic findings because of the complexity of protein activities and the rarity of animal models that fully recapitulate human conditions. Many genes contributing to the visual cycle are associated with inherited retinal diseases such as LCA, rod-cone dystrophy, and a juvenile form of macular degeneration called Stargardt disease (Figure 3) (Hussain et al, 2018;Kiser and Palczewski, 2016;Travis et al, 2007;Tsin et al, 2018). In the simplest case the mutation of a gene can lead to a loss of function (LoF); for example, an inactivating mutation in RDH5 abrogates RDH activity and leads to the disease known as Fundus albipunctatus, characterized by delayed dark adaptation and the appearance of white flecks in the retina (Dryja, 2000;Yamamoto et al, 1999) (Figures 3A and 3B).…”

“…However, clinical trials on RPE65 gene augmentation therapy showed a significant but modest improvement in retinal function (Bainbridge et al, 2008;Maguire et al, 2008) and fading effects in patients (Maguire et al, 2009). Mutations in the gene encoding the ATP-binding cassette subfamily A member 4 (ABCA4) transporter are the most frequent mutations associated with Stargardt disease and also can cause some forms of autosomal recessive cone-rod dystrophy (not shown in Figure 3) (Paloma et al, 2001;Rozet et al, 1998) and arRP (Allikmets et al, 1997) (reviewed in (Hussain et al, 2018;Kiser and Palczewski, 2016;Molday, 2015;Travis et al, 2007;Tsin et al, 2018;Tsybovsky et al, 2010)). These examples point to the simple fact that mutations in many genes can result in clinically similar disease phenotypes, and that mutations in one gene can manifest in different forms of retinal disease.…”