*5.6. RPGR*

Retinitis pigmentosa GTPase regulator (RPGR) localizes to the connecting cilium and mutations within the *RPGR* gene account for >80% of X-linked RP (XLRP). There are two major retinal isoforms, one encoded by exons 1–19 and a second isoform that consists of exons 1–15 and a retained portion of intron 15 (ORF15; see [108] for a summary). ORF15 is a mutation hotspot [109]. Three different *Rpgr* mutations cause X-linked retinal degeneration in dogs. One is caused by a genomic deletion [110] and two are due to microdeletions in ORF15 and provide two distinct mechanistic models for RPGR-XLRP [111]. The first, known in the dog as XLPRA1, has a 5 bp deletion and a premature stop codon [111]. This is a relatively late onset and slowly progressive degeneration [112]. The second form, XLPRA2, has a 2 bp deletion with a frameshift resulting in the addition of 34 basic residues. In vitro studies showed that the mutant protein aggregated in the endoplasmic reticulum and is hypothesized to have a toxic effect [111]. The phenotype presents as an early onset degeneration with early changes being outer segmen<sup>t</sup> disruption and opsin (rod and cone) mislocalization. Photoreceptor cell death was shown to occur in a biphasic manner with two distinct phases of cell death with evidence of remodeling occurring [113]. Studies of the heterozygous females revealed that there are patches of diseased retina, presumably resulting from regions where random X-inactivation has resulted in expression of the mutant allele and patches of unaffected retina (where the wildtype allele is expressed). In the earlier onset XLPRA2 migration of adjacent photoreceptors into regions where rod photoreceptors died occurs, showing retinal plasticity in the younger animals. This remodeling was not described in the XLPRA1, where patches of degeneration occur at a later age [114].
