title: Human cone photoreceptor dependence on RPE65 isomerase.
abstract: The visual (retinoid) cycle, the enzymatic pathway that regenerates chromophore after light absorption, is located primarily in the retinal pigment epithelium (RPE) and is essential for rod photoreceptor survival. Whether this pathway also is essential for cone photoreceptor survival is unknown, and there are no data from man or monkey to address this question. The visual cycle is naturally disrupted in humans with Leber congenital amaurosis (LCA), which is caused by mutations in RPE65, the gene that encodes the retinoid isomerase. We investigated such patients over a wide age range (3-52 years) for effects on the cone-rich human fovea. In vivo microscopy of the fovea showed that, even at the youngest ages, patients with RPE65-LCA exhibited cone photoreceptor loss. This loss was incomplete, however, and residual cone photoreceptor structure and function persisted for decades. Basic questions about localization of RPE65 and isomerase activity in the primate eye were addressed by examining normal macaque. RPE65 was definitively localized by immunocytochemistry to the central RPE and, by immunoblotting, appeared to concentrate in the central retina. The central retinal RPE layer also showed a 4-fold higher retinoid isomerase activity than more peripheral RPE. Early cone photoreceptor losses in RPE65-LCA suggest that robust RPE65-based visual chromophore production is important for cones; the residual retained cone structure and function support the speculation that alternative pathways are critical for cone photoreceptor survival.
authors.affiliation: Scheie Eye Institute, Department of Ophthalmology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. jacobsos@mail.med.upenn.edu
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
authors.forename: Tomas S
authors.initials: TS
authors.lastname: Aleman
authors.forename: Artur V
authors.initials: AV
authors.lastname: Cideciyan
authors.forename: Elise
authors.initials: E
authors.lastname: Heon
authors.forename: Marcin
authors.initials: M
authors.lastname: Golczak
authors.forename: William A
authors.initials: WA
authors.lastname: Beltran
authors.forename: Alexander
authors.initials: A
authors.lastname: Sumaroka
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Schwartz
authors.forename: Alejandro J
authors.initials: AJ
authors.lastname: Roman
authors.forename: Elizabeth A M
authors.initials: EA
authors.lastname: Windsor
authors.forename: James M
authors.initials: JM
authors.lastname: Wilson
authors.forename: Gustavo D
authors.initials: GD
authors.lastname: Aguirre
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Stone
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D005136:Eye Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008875:Middle Aged; D029242:Optic Atrophy, Hereditary, Leber / Q000378:metabolism; D010857:Pigment Epithelium of Eye / Q000201:enzymology* / Q000378:metabolism; D017949:Retinal Cone Photoreceptor Cells / Q000502:physiology*; D019745:cis-trans-Isomerases / Q000235:genetics / Q000378:metabolism*; D000099178:Retinoid Isomerohydrolase
chemical_list: D002352:Carrier Proteins; D005136:Eye Proteins; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase