RPGR: role in the photoreceptor cilium, human retinal disease, and gene therapy.

Cilia are specialized dynamic organelles extending from the surface of almost all mammalian cells. Since proteins and protein precursors are transported across the ciliary compartments via intraflagellar transport (IFT), mutations in genes encoding proteins that participate in IFT can cause a spectrum of different ciliopathies. Photoreceptors of the mammalian retina contain ciliary structures that connect the inner (IS) with the outer segments (OS). This structure, the connecting cilium (CC), serves as the only junction between OS and IS, the correct passage of proteins through the CC is crucial for the functioning and maintenance of the cells. Therefore, any impairment of the IFT leads to severe malfunction of photoreceptors, and may induce apoptosis ultimately leading to the degeneration of the retina. The Retinitis Pigmentosa GTPase Regulator (RPGR), which is located in the CC, participates in the IFT and interacts with a variety of proteins, including RPGRIP-1, CEP290, NPM, SMC1 and 3 and IFT88. However, the function of RPGR through its interaction with these proteins is not yet entirely understood. Mutations in the RPGR gene lead to X-linked Retinitis pigmentosa (XLRP), one of the most severe and early onset forms of RP. Gene therapy is considered a potential therapeutic option and is currently under investigation in several animal models of XLRP. However, some of the currently available mouse models are only partially suitable for the development of therapeutic strategies and the quest for more appropriate small animal models is still an issue.