title: Variegated yet non-random rod and cone photoreceptor disease patterns in RPGR-ORF15-associated retinal degeneration.
abstract: Mutations in the ORF15 exon of the RPGR gene cause a common form of X-linked retinitis pigmentosa, which often results in severe loss of vision. In dogs and mice, gene augmentation therapy has been shown to arrest the progressive degeneration of rod and cone photoreceptors. However, the distribution of potentially treatable photoreceptors across the human retinas and the rate of degeneration are not known. Here, we have defined structural and functional features of the disease in 70 individuals with ORF15 mutations. We also correlated the features observed in patients with those of three Rpgr-mutant (Rpgr-ko, Rd9, and Rpgr-cko) mice. In patients, there was pronounced macular disease. Across the retina, rod and cone dysfunction showed a range of patterns and a spectrum of severity between individuals, but a high symmetry was observed between eyes of each individual. Genotype was not related to disease expression. In the Rpgr-ko mice, there were intra-retinal differences in rhodopsin and cone opsin trafficking. In Rd9 and Rpgr-cko mice, retinal degeneration showed inter-ocular symmetry. Longitudinal results in patients revealed localized rod and cone dysfunction with progression rates of 0.8 to 1.3 log per decade in sensitivity loss. Relatively retained rod and cone photoreceptors in mid- and far-peripheral temporal-inferior and nasal-inferior visual field regions should be good targets for future localized gene therapies in patients.
authors: Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, PA, USA.
authors: Jason
authors: J
authors: Charng
authors: Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, PA, USA.
authors: Artur V
authors: AV
authors: Cideciyan
authors: Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, PA, USA.
authors: Samuel G
authors: SG
authors: Jacobson
authors: Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, PA, USA.
authors: Alexander
authors: A
authors: Sumaroka
authors: Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, PA, USA.
authors: Sharon B
authors: SB
authors: Schwartz
authors: Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, PA, USA.
authors: Malgorzata
authors: M
authors: Swider
authors: Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, PA, USA.
authors: Alejandro J
authors: AJ
authors: Roman
authors: Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, PA, USA.
authors: Rebecca
authors: R
authors: Sheplock
authors: Department of Ophthalmology, University of Massachusetts Medical School, Worcester, Massachusetts, MA, USA.
authors: Manisha
authors: M
authors: Anand
authors: Retina Associates of Florida, Tampa, Florida, FL, USA.
authors: Marc C
authors: MC
authors: Peden
authors: Department of Ophthalmology, University of Massachusetts Medical School, Worcester, Massachusetts, MA, USA.
authors: Hemant
authors: H
authors: Khanna
authors: Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
authors: Elise
authors: E
authors: Heon
authors: MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Edinburgh, Scotland, UK.
authors: Alan F
authors: AF
authors: Wright
authors: Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland, MD, USA.
authors: Anand
authors: A
authors: Swaroop
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002648:Child; D005136:Eye Proteins / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009154:Mutation; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism / Q000473:pathology; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism / Q000473:pathology; D041441:Retinoschisis / Q000235:genetics* / Q000473:pathology; D012243:Rhodopsin / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D005136:Eye Proteins; C099929:RPGR protein, human; D012243:Rhodopsin