Cone versus Rod Disease in a Mutant Rpgr Mouse Caused by Different Genetic Backgrounds

PURPOSE. To establish mouse models for RPGR-associated diseases by generating and characterizing an Rpgr mutation (inframe deletion of exon 4) in two different genetic backgrounds (BL/6 and BALB/c). METHODS. Gene targeting in embryonic stem (ES) cells was performed to introduce a in-frame deletion of exon 4 in the Rpgr gene (Rpgr(Delta Ex4)). Subsequently, the mutation was introduced in two different inbred mouse strains by successive breeding. Mutant and wild-type mice of both strains were characterized by electroretinography (ERG) and histology at five time points (1, 3, 6, 9, and 12 months). RPGR transcript amounts were assessed by quantitative RT-PCR. A variety of photoreceptor proteins, including RPGR-ORF15, RPGRIP, PDE6 delta/PrBP delta, rhodopsin, and cone opsin, were localized on retinal sections by immunohistochemistry. RESULTS. Mislocalization of rhodopsin and cone opsin was an early pathologic event in mutant mice of both lines. In contrast, RPGR-ORF15 as well as RPGRIP1 and PDE6 delta/PrBP delta showed similar localizations in mutant and wild-type animals. Functional and histologic studies revealed a mild rod-dominated phenotype in mutant male mice on the BL/6 background, whereas a cone-dominated phenotype was observed for the same mutation in the BALB/c background. CONCLUSIONS. Both Rpgr mutant mouse lines developed retinal disease with a striking effect of the genetic background. Conespecific modifiers might influence the retinal phenotype in the BALB/c strain. The two lines provide models to study RPGR function in rods and cones, respectively. (Invest Ophthalmol Vis Sci. 2010;51:1106-1115) DOI:10.1167/iovs.08-2742