Retinal Degenerative Diseases pp 29-33
RCC1-Like Domain and ORF15: Essentials in RPGR Gene
- Cite this paper as:
- Jin ZB., Hayakawa M., Murakami A., Nao-i N. (2006) RCC1-Like Domain and ORF15: Essentials in RPGR Gene. In: Hollyfield J.G., Anderson R.E., LaVail M.M. (eds) Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology, vol 572. Springer, Boston, MA
Retinitis Pigmentosa (RP) is a group of disease with progressive degeneration of photoreceptor. Patients present with night blindness, progressive loss of peripheral vision, and pigmentary alterations in the retina with the appearance of “bone-spicules”. X-Linked Retinitis Pigmentosa (XLRP) accounts for about 15–30% of all RP cases1, 2, 3, 4, and produces severe symptoms, with early onset and rapid deterioration. Five XLRP-related loci, RP2, RP3, RP6, RP23 and RP24, were mapped on the X chromosome through linkage analyses. RP3 and RP2 account for 56–90% and 10–20% of XLRP, respectively.5, 6, 7, 8, 9 The two major loci, RP2 and RPGR (RP3) genes, have been cloned successfully.10, 11, 12, 13 Retinitis Pigmentosa GTPase Regulator (RPGR), locus on the X chromosome (Xp21.1), accounted for about 30– 60% of XLRP cases in molecular screening studies.13, 14 Positional cloning of the RPGR gene originally revealed a 2784-nucleotide (nt) ubiquitously expressed transcript which include 19 exons coding for 815 amino acids. Exon ORF15 which was identified later, encodes 567 amino acids, and was shown to be a mutation hot spot. Disease-causing mutations reported so far are localized in 5-prime exons and ORF15, while none have been reported in exons 16–19. The N-terminal sequence of RPGR spanning exons 1–11 shows homology to the regulator of chromatin condensation (RCC1)10, a nuclear protein that catalyzes guanine nucleotide exchange for the small GTPase Ran and regulates nuclear import and export.15 On the basis of RCC1 crystal structure, the RPGR protein is predicted to have a seven-blade beta-propeller structure and to function as a GEF for a small GTP-binding protein. The mutations exclusively affect the RCC1-like domain (RLD) of RPGR and ORF15, which suggests that these regions are contribute to the physiological role of RPGR in the retina. Although a growing number of novel mutations of RPGR are being reported, its function in vivo is still unclear. Through a yeast two-hybrid screens, two proteins, the delta subunit of rod cyclic GMP phosphodiesterase (PDEδ) and RPGR interaction protein (RPGRIP1), were identified to interact with the RLD of RPGR.16, 17, 18
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