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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.

Loss of human disease protein retinitis pigmentosa GTPase regulator (RPGR) differentially affects rod or cone-enriched retina