title: Loss of human disease protein retinitis pigmentosa GTPase regulator (RPGR) differentially affects rod or cone-enriched retina.
abstract: It is unclear how genes, such as RPGR (retinitis pigmentosa guanine triphosphatase regulator) that are expressed in both rods and cones, cause variable disease pathogenesis. Using transcriptomic analysis, we show that loss of RPGR in a rod-dominant mouse retina (Rpgr(ko)) results in predominant alterations in genes involved in actin cytoskeletal dynamics, prior to onset of degeneration. We validated these findings and found an increase in activated RhoA-GTP levels and polymerized F-actin in the Rpgr(ko) mouse retina. To assess the effect of the loss of RPGR in the all-cone region of the human retina, we used Nrl(-/-) (neural retina leucine zipper) mice, to generate Rpgr(ko)::Nrl(-/-) double-knock-out (Rpgr-DKO) mice. These mice exhibited supranormal cone response to light and substantially retained retinal architecture. Transcriptomic analysis revealed predominant up-regulation of retinal pigmented epithelium (RPE)-specific genes associated with visual cycle, whereas fatty acid analysis showed mild decrease in docosahexaenoic acid in the retina of the Rpgr-DKO mice when compared with the Nrl(-/-) mice. Our data reveal new insights into distinct intracellular pathways that are involved in RPGR-associated rod and cone dysfunction and provide a platform to design new treatment modalities.
authors.affiliation: Department of Ophthalmology, University of Massachusetts Medical School, 368 Plantation St, Albert Sherman Center AS6-2043, Worcester, MA 01605, USA and.
authors.forename: Kollu N
authors.initials: KN
authors.lastname: Rao
authors.affiliation: Department of Ophthalmology, University of Massachusetts Medical School, 368 Plantation St, Albert Sherman Center AS6-2043, Worcester, MA 01605, USA and.
authors.forename: Linjing
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Ophthalmology, University of Massachusetts Medical School, 368 Plantation St, Albert Sherman Center AS6-2043, Worcester, MA 01605, USA and.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Brush
authors.affiliation: University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Raju V S
authors.initials: RV
authors.lastname: Rajala
authors.affiliation: Department of Ophthalmology, University of Massachusetts Medical School, 368 Plantation St, Albert Sherman Center AS6-2043, Worcester, MA 01605, USA and hemant.khanna@umassmed.edu.
authors.forename: Hemant
authors.initials: H
authors.lastname: Khanna
mesh_terms: D008841:Actin Cytoskeleton / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics*; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism* / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism* / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000378:metabolism / Q000473:pathology
chemical_list: D002352:Carrier Proteins; D005136:Eye Proteins; C513598:RPGR protein, mouse