The retinitis pigmentosa GTPase regulator, RPGR, intellects with the deltasubunit of rod cyclic GMP phosphodiesterase

Recently, the retinitis pigmentosa 3 (RP3) gene has been cloned and named r etinitis pigmentosa GTPase regulator (RPGR). The amino-terminal half of RPG R is homologous to regulator of chromosome condensation (RCC1), the nucleot ide exchange factor for the small GTP-binding protein Ran. In a yeast-two-h ybrid screen me identified the delta subunit of rod cyclic GMP phosphodiest erase (PDE delta) as interacting with the RCC1-Iike domain (RLD) of RPGR (R pGR(392)). The interaction of RPGR with PDE delta was confirmed by pull-dow n assays and plasmon surface resonance. The binding affinity mas determined to be 90 nM. Six missense mutations at evolutionary conserved residues wit hin the RLD, which were found in RP3 patients, were analyzed by using the t wo-hybrid system, All missense mutations showed reduced interaction with PD E delta, A non-RP3-associated missense substitution outside the RLD, V36F, did not abolish the interaction with PDE delta, PDE delta is widely express ed and highly conserved across evolution and is proposed to regulate the me mbrane insertion or solubilization of prenylated proteins, including the ca talytic subunits of the PDE holoenzyme involved in phototransduction and sm all GTP-binding proteins of the Rab family. These results suggest that RPGR mutations give rise to retinal degeneration by dysregulation of intracellu lar processes that determine protein localization and protein transport.