RPE65 (retinoid isomerohydrolase RPE65; HGNC:10294, NCBI Gene ID 6121) is a human locus mapped to chromosome band 1p31.3 that encodes retinoid isomerohydrolase RPE65 (533 aa; EC 3.1.1.64). RPE65 acts in retinoid visual cycle (all-trans-retinyl ester to 11-cis-retinol isomerization), together with Rhodopsin (RHO Photoreceptor), CEP290 Retinal Ciliopathy Gene, and Photoreceptor System. Encodes the retinal pigment epithelium isomerohydrolase regenerating 11-cis-retinal; target of Luxturna gene therapy.
Retinoid visual cycle (all-trans-retinyl ester to 11-cis-retinol isomerization)
Clinical / Therapeutic Role
Leber congenital amaurosis type 2 (LCA2); target of FDA-approved voretigene neparvovec (Luxturna)
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 14-exon gene on chromosome 1p31.3 encoding a 533-amino-acid non-heme iron(II)-dependent peripheral membrane enzyme of the carotenoid oxygenase superfamily coordinated by four conserved histidine residues.
Cellular & Tissue Expression Profile: Expressed almost exclusively in the smooth endoplasmic reticulum of retinal pigment epithelium (RPE) cells immediately adjacent to rod and cone photoreceptor outer segments.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Catalyzes the rate-limiting isomerohydrolase step of the vertebrate visual cycle, cleaving and isomerizing all-trans-retinyl fatty acid esters into 11-cis-retinol, which is subsequently oxidized to 11-cis-retinal and shuttled back to photoreceptors to recombine with opsin and regenerate photoactive rhodopsin (RHO).
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Biallelic loss-of-function mutations in RPE65 abolish 11-cis-retinal regeneration while causing toxic accumulation of all-trans-retinyl esters in the RPE, resulting in Leber congenital amaurosis type 2 (LCA2) or early-onset autosomal recessive retinitis pigmentosa type 20 with profound nyctalopia (night blindness) and progressive photoreceptor degeneration.
Therapeutic & Clinical Pharmacology: In December 2017, subretinal AAV2-hRPE65v2 (voretigene neparvovec-rzyl / Luxturna) became the first in vivo gene therapy approved by the US FDA for an inherited genetic disease, restoring functional vision in patients with biallelic RPE65 mutations.