RPE65

Official Full Name

retinoid isomerohydrolase RPE65

Organism

Homo sapiens

GeneID

6121

Background

The protein encoded by this gene is a component of the vitamin A visual cycle of the retina which supplies the 11-cis retinal chromophore of the photoreceptors opsin visual pigments. It is a member of the carotenoid cleavage oxygenase superfamily. All members of this superfamily are non-heme iron oxygenases with a seven-bladed propeller fold and oxidatively cleave carotenoid carbon:carbon double bonds. However, the protein encoded by this gene has acquired a divergent function that involves the concerted O-alkyl ester cleavage of its all-trans retinyl ester substrate and all-trans to 11-cis double bond isomerization of the retinyl moiety. As such, it performs the essential enzymatic isomerization step in the synthesis of 11-cis retinal. Mutations in this gene are associated with early-onset severe blinding disorders such as Leber congenital. [provided by RefSeq, Oct 2017]

Synonyms

p63; BCO3; LCA2; RP20; rd12; mRPE65; sRPE65;

Bio Chemical Class

Carboxylic ester hydrolase

Protein Sequence

MSIQVEHPAGGYKKLFETVEELSSPLTAHVTGRIPLWLTGSLLRCGPGLFEVGSEPFYHLFDGQALLHKFDFKEGHVTYHRRFIRTDAYVRAMTEKRIVITEFGTCAFPDPCKNIFSRFFSYFRGVEVTDNALVNVYPVGEDYYACTETNFITKINPETLETIKQVDLCNYVSVNGATAHPHIENDGTVYNIGNCFGKNFSIAYNIVKIPPLQADKEDPISKSEIVVQFPCSDRFKPSYVHSFGLTPNYIVFVETPVKINLFKFLSSWSLWGANYMDCFESNETMGVWLHIADKKRKKYLNNKYRTSPFNLFHHINTYEDNGFLIVDLCCWKGFEFVYNYLYLANLRENWEEVKKNARKAPQPEVRRYVLPLNIDKADTGKNLVTLPNTTATAILCSDETIWLEPEVLFSGPRQAFEFPQINYQKYCGKPYTYAYGLGLNHFVPDRLCKLNVKTKETWVWQEPDSYPSEPIFVSHPDALEEDDGVVLSVVVSPGAGQKPAYLLILNAKDLSEVARAEVEINIPVTFHGLFKKS

Open

Disease

Herpes simplex infection, Inherited retinal dystrophy, Macular degeneration, Retinopathy, Vision impairment

Approved Drug

Clinical Trial Drug

5 +

Discontinued Drug

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Detailed Information

The RPE65 (Retinoid Isomerohydrolase RPE65) gene is located on chromosome 1p31 and encodes a 533-amino-acid protein with a molecular weight of approximately 65 kDa, specifically expressed in retinal pigment epithelium (RPE) cells. This protein belongs to the carotenoid cleavage oxygenase superfamily and features a distinctive seven-bladed β-propeller domain, though its function differs significantly from other family members. RPE65 is a core enzyme in the visual cycle, catalyzing the hydrolysis and isomerization of all-trans retinyl esters into 11-cis retinol, a critical step for regenerating visual pigments in rod and cone photoreceptors. This reaction provides the essential chromophore, 11-cis retinal, necessary for phototransduction.

The visual cycle is a complex biochemical process that begins with the photoisomerization of 11-cis retinal to all-trans retinal upon light absorption, followed by the release of all-trans retinal from opsin. In photoreceptor cells, all-trans retinal is reduced to all-trans retinol, which is then transported to adjacent RPE cells. Within RPE cells, lecithin retinol acyltransferase (LRAT) esterifies all-trans retinol to form all-trans retinyl esters, serving as the substrate for RPE65. Acting as an isomerohydrolase, RPE65, in conjunction with its bound Fe²⁺ ion, catalyzes the hydrolysis and isomerization of all-trans retinyl esters to 11-cis retinol. The 11-cis retinol is subsequently oxidized by 11-cis retinol dehydrogenase (RDH5) to 11-cis retinal, which is transported back to photoreceptor cells, completing the visual cycle. RPE65 exists in two forms: a soluble form that binds vitamin A and a palmitoylated membrane-bound form that binds all-trans retinyl esters, coordinating to ensure continuous regeneration of visual pigments.

Beyond its classical role in vision, RPE65 can catalyze the isomerization of lutein to meso-zeaxanthin, an eye-specific carotenoid localized in the macula that contributes to blue-light filtering and antioxidant protection. This expanded function highlights RPE65’s broader biological significance and provides new insights for studying age-related macular degeneration.

Figure 1. Dual roles of RPE65 showing its canonical function in the visual cycle and its role in lutein isomerization to meso-zeaxanthin in the RPE. (Redmond TM. et al., 2017)

Pathogenic Mutations and Clinical Phenotypes

Mutations in the RPE65 gene cause autosomal recessive inherited retinal dystrophies, collectively referred to as RPE65-associated inherited retinal diseases (RPE65-IRD). These include Leber congenital amaurosis type 2 (LCA2), severe early-onset retinal dystrophy (SECORD and EOSRD), and retinitis pigmentosa type 20 (RP20), representing a continuous clinical spectrum associated with the same causative gene. RPE65-IRD typically manifests from birth to age five, with core clinical features including night blindness, nystagmus, progressive visual field loss, and central vision impairment. As the disease progresses, visual acuity declines, color vision deteriorates, and patients may ultimately become completely blind. The proportion of patients meeting World Health Organization blindness criteria increases with age, reaching 100% after age 40. Early severe vision loss may also lead to delays in language, social, and behavioral development in approximately 30% of affected children.

Clinical heterogeneity among RPE65-IRD patients is significant. LCA2 patients often exhibit severe visual impairment within the first year of life, while RP20 patients may present initially with night blindness and progress to complete blindness over decades. This variability is partly due to the type of RPE65 mutation—missense, nonsense, splicing, or insertion/deletion—and the residual enzymatic activity. Over 120 pathogenic RPE65 mutations have been reported globally, distributed across 14 exons, with specific single-nucleotide polymorphisms (SNPs) in exons 10 and 11 identified as potentially valuable for genetic screening in Chinese populations. Pathologically, RPE65 mutations result in enzymatic loss-of-function, interrupting 11-cis retinal production and preventing visual pigment regeneration. Even with intact photoreceptor structure, this functional loss leads to progressive photoreceptor apoptosis. Electroretinography (ERG) shows markedly reduced or absent scotopic and photopic responses, optical coherence tomography (OCT) reveals thinning of the outer retina, and fundus autofluorescence (FAF) imaging demonstrates characteristic hypoautofluorescence, correlating with visual impairment and disease progression.

Gene Therapy Advances and Clinical Translation

Understanding the pathogenic mechanism of RPE65-IRD has enabled gene replacement therapy as the most promising treatment approach. This strategy delivers a functional RPE65 gene to RPE cells using recombinant adeno-associated virus (AAV) vectors to restore visual cycle activity. In 2017, the first RPE65 gene therapy product, voretigene neparvovec (Luxturna), received FDA approval, marking a milestone in the treatment of inherited retinal diseases. Using an AAV2 vector, Luxturna demonstrated significant visual improvement in 93% of patients in phase III trials, with a mean increase of 1.8 log units in multi-luminance mobility testing (MLMT) and efficacy sustained for at least four years.

However, AAV2 vectors face limitations including moderate transduction efficiency and high dosing requirements, which may increase intraocular inflammation and retinal structural risk. To address these challenges, next-generation vectors are in development. HG004, an AAV9-based therapy, showed superior preclinical efficacy in Rpe65 knockout mouse models, achieving a 67.6% retinal function recovery at week 17 compared to 35.8% with AAV2, while requiring approximately 1/25 of the Luxturna vector dose, potentially reducing immune-related and ocular adverse events. In 2023, HG004 received FDA orphan drug and rare pediatric disease designations, with international multi-center phase I/II trials underway to evaluate safety, tolerability, and efficacy up to 52 weeks, including MLMT for visual function assessment. Early clinical data in China indicate rapid and significant vision improvement within seven days after a single low-dose injection.

Combination therapies are also under exploration. Oral 9-cis retinal (QLT091001) bypasses the RPE65 defect by providing 11-cis retinal precursors directly, improving vision in 80% of LCA2 patients in phase II trials. Optogenetic approaches confer light sensitivity to remaining retinal ganglion cells, offering an alternative treatment for late-stage patients. These developments collectively advance precision medicine for RPE65-associated retinal diseases, offering potential functional vision restoration even in patients with severe or advanced retinal degeneration.

Reference

Stingl K, Priglinger C, Herrmann P. RPE65-Associated Retinal Dystrophies: Phenotypes and Treatment Effects with Voretigene Neparvovec. Klin Monbl Augenheilkd. 2024 Mar;241(3):259-265.
Uppal S, Poliakov E, Gentleman S, et al. RPE65 Palmitoylation: A Tale of Lipid Posttranslational Modification. Adv Exp Med Biol. 2019;1185:537-541.
Redmond TM. RPE65 takes on another role in the vertebrate retina. Proc Natl Acad Sci USA. 2017 Oct 10;114(41):10818-10820.

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