Purpose: In humans, over 80% of X- linked retinitis pigementosa (XLRP) is caused by mutations in RPGR. RPGR associated disease is clinically heterogeneous, indicating involvement of genes that can influence the associated phenotype. RPGR is known to interact with selected ciliary proteins including CEP290, RPGRIP1, NPHP1, NPHP4 and NPHP5. The purpose of this study is to assess the contribution of these RPGR-interacting proteins on the severity of RPGR-associated retinal degeneration in Rpgrko mice.

Methods: Rpgrko female mice were bred with male Cep290rd16/rd16, Nphp1-/-, Nphp4nmf192, Nphp5-/-, Rpgrip1-/-. Males from F1 generation with genotype RpgrKO/Cep290+/rd16, Rpgrko/Nphp1+/-, Rpgrko/Nphp4nmf192/+, Rpgrko/Nphp5+/-, Rpgrko/Rpgrip1+/- were selected for further analysis. Structural and function studies were performed using Histology, transmission electron microscopy (TEM), immunofluorescence staining, and Electroretinopgraphy (ERG).

Results: The Rpgrko mice exhibit degeneration of retina and relatively mild decrease in cone and rod function by 6 months of age. Our analysis of double mutant mice revealed that Rpgrko/Cep290+/rd16 exhibit accelerated retinal degeneration as compared to Rpgrko mice. TEM analysis of Rpgrko/Cep290+/rd16 retina showed vesicle accumulation at the base of the outer segments of photoreceptors, which were not detected in the Rpgrko mice. We also detected decreased cone-specific staining of M-opsin. No significant effect on the retina was observed in RpgrKO/Nphp1+/-, RpgrKO/Nphp4nmf192/+, Rpgrko/Nphp5+/-, Rpgrko/Rpgrip1+/- (n=3) mice up to 6 months of age, as compared to Rpgrko.

Conclusions: Our studies suggest that mutations in CEP290 can potentially influence the severity of retinal phenotype due to mutations in RPGR. Further studies are in progress to assess the influence of additional RPGR-interacting proteins on RPGR-disease.