Retinitis pigmentosa GTPase regulator explained

X-linked retinitis pigmentosa GTPase regulator is a GTPase-binding protein that in humans is encoded by the RPGR gene.^{[1] [2] [3] [4]} The gene is located on the X-chromosome and is commonly associated with X-linked retinitis pigmentosa (XLRP). In photoreceptor cells, RPGR is localized in the connecting cilium which connects the protein-synthesizing inner segment to the photosensitive outer segment and is involved in the modulation of cargo trafficked between the two segments.^[5]

Function

This gene encodes a protein with a series of six RCC1-like domains (RLDs), characteristic of the highly conserved guanine nucleotide exchange factors. Mutations in this gene have been associated with X-linked retinitis pigmentosa (XLRP). Multiple alternatively spliced transcript variants that encode different isoforms of this gene have been reported, but the full-length natures of only some have been determined.

The two major isoforms are RPGR^const, the default isoform, composed of exons 1-19, and RPGR^ORF15 which retains part of intron 15 as the terminal exon. ORF15 is the terminal exon of RPGR^ORF15 and is a mutational hotspot accounting for ~60% of RPGR patients with heterogeneous diseases ranging from XLRP to cone-rod degeneration and macular degeneration.^[6] Alternatively, the RPGR^const isoform contains a putative prenylation domain on its C-terminal end which is involved in posttranslational modification and allows membrane-association and protein trafficking.^[7] The C-terminal domain of the RPGR^const isoform contains a CTIL motif (812CTIL815) which recruits prenyl-binding protein PDE6D which then shuttles the protein to the connecting cilium.^[8]

Photoreceptor cells contain an inner segment and an outer segment which are joined by a connecting cilium. Protein synthesis occurs exclusively in the inner segment and all proteins must be trafficked across the connecting cilium to the outer segment where the phototransduction cascade takes place. RPGR is primarily located in a protein complex in the connecting cilium and is involved in regulating the cargo that is trafficked from the inner segment to the outer segment.

Interactions

Retinitis pigmentosa GTPase regulator has been shown to interact with PDE6D^[9] nephronophthisis (NPHP) proteins^[10] and RPGRIP1.^[11] Binding to PDE6D has been shown to ensure ciliary localization of the RPGR^const isoform.^[12] Additionally, the N-terminal of interacts with a PDE6D interacting protein, INPP5E (inositol polyphosphatase 5E). INPP5E has been shown to regulates phosphoinositide metabolism and may modulate the phosphoinositide content of photoreceptor cells.

RPGR has also been shown to preferentially interact with the GDP-bound form of the small GTPase RAB8A.^[13] RAB8A is involved in rhodopsin trafficking in primary cilia.^[14] The C-terminal domain of RPGR^ORF15 has been shown to interact with whirlin, a ciliary protein that is mutated in Usher Syndrome.^[15] The RPGR^ORF15 isoform has been shown to be glutamylated on its N-terminus by tubulin-tyrosine ligase-like 5 (TTLL5).^[16] It has also been shown that loss of TTLL5 mimics loss of RPGR in the mouse retina.

See also

• X-linked cone-rod dystrophy, type 1

Further reading

• Book: Jin ZB, Hayakawa M, Murakami A, Nao-i N . RCC1-like domain and ORF15: essentials in RPGR gene . 572 . 29–33 . 2007 . 17249551 . 10.1007/0-387-32442-9_5 . 978-0-387-28464-4 . Advances in Experimental Medicine and Biology . Retinal Degenerative Diseases . registration .
• Ott J, Bhattacharya S, Chen JD, Denton MJ, Donald J, Dubay C, Farrar GJ, Fishman GA, Frey D, Gal A . Localizing multiple X chromosome-linked retinitis pigmentosa loci using multilocus homogeneity tests . Proceedings of the National Academy of Sciences of the United States of America . 87 . 2 . 701–4 . Jan 1990 . 2300556 . 53333 . 10.1073/pnas.87.2.701 . 1990PNAS...87..701O . free .
• McGuire RE, Sullivan LS, Blanton SH, Church MW, Heckenlively JR, Daiger SP . X-linked dominant cone-rod degeneration: linkage mapping of a new locus for retinitis pigmentosa (RP 15) to Xp22.13-p22.11 . American Journal of Human Genetics . 57 . 1 . 87–94 . Jul 1995 . 7611300 . 1801245 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . Jan 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Research . 6 . 9 . 791–806 . Sep 1996 . 8889548 . 10.1101/gr.6.9.791 . free .
• Fujita R, Buraczynska M, Gieser L, Wu W, Forsythe P, Abrahamson M, Jacobson SG, Sieving PA, Andréasson S, Swaroop A . Analysis of the RPGR gene in 11 pedigrees with the retinitis pigmentosa type 3 genotype: paucity of mutations in the coding region but splice defects in two families . American Journal of Human Genetics . 61 . 3 . 571–80 . Sep 1997 . 9326322 . 1715956 . 10.1086/515523 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . Oct 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Buraczynska M, Wu W, Fujita R, Buraczynska K, Phelps E, Andréasson S, Bennett J, Birch DG, Fishman GA, Hoffman DR, Inana G, Jacobson SG, Musarella MA, Sieving PA, Swaroop A . Spectrum of mutations in the RPGR gene that are identified in 20% of families with X-linked retinitis pigmentosa . American Journal of Human Genetics . 61 . 6 . 1287–92 . Dec 1997 . 9399904 . 1716085 . 10.1086/301646 .
• Hardcastle AJ, David-Gray ZK, Jay M, Bird AC, Bhattacharya SS . Localization of CSNBX (CSNB4) between the retinitis pigmentosa loci RP2 and RP3 on proximal Xp . Investigative Ophthalmology & Visual Science . 38 . 13 . 2750–5 . Dec 1997 . 9418727 .
• Yan D, Swain PK, Breuer D, Tucker RM, Wu W, Fujita R, Rehemtulla A, Burke D, Swaroop A . Biochemical characterization and subcellular localization of the mouse retinitis pigmentosa GTPase regulator (mRpgr) . The Journal of Biological Chemistry . 273 . 31 . 19656–63 . Jul 1998 . 9677393 . 10.1074/jbc.273.31.19656 . free .
• Fishman GA, Grover S, Jacobson SG, Alexander KR, Derlacki DJ, Wu W, Buraczynska M, Swaroop A . X-linked retinitis pigmentosa in two families with a missense mutation in the RPGR gene and putative change of glycine to valine at codon 60 . Ophthalmology . 105 . 12 . 2286–96 . Dec 1998 . 9855162 . 10.1016/S0161-6420(98)91231-3 .
• Linari M, Ueffing M, Manson F, Wright A, Meitinger T, Becker J . The retinitis pigmentosa GTPase regulator, RPGR, interacts with the delta subunit of rod cyclic GMP phosphodiesterase . Proceedings of the National Academy of Sciences of the United States of America . 96 . 4 . 1315–20 . Feb 1999 . 9990021 . 15460 . 10.1073/pnas.96.4.1315 . 1999PNAS...96.1315L . free .
• Dry KL, Manson FD, Lennon A, Bergen AA, Van Dorp DB, Wright AF . Identification of a 5' splice site mutation in the RPGR gene in a family with X-linked retinitis pigmentosa (RP3) . Human Mutation . 13 . 2 . 141–5 . 1999 . 10094550 . 10.1002/(SICI)1098-1004(1999)13:2<141::AID-HUMU6>3.0.CO;2-Q . 34407949 . free .
• Kirschner R, Rosenberg T, Schultz-Heienbrok R, Lenzner S, Feil S, Roepman R, Cremers FP, Ropers HH, Berger W . RPGR transcription studies in mouse and human tissues reveal a retina-specific isoform that is disrupted in a patient with X-linked retinitis pigmentosa . Human Molecular Genetics . 8 . 8 . 1571–8 . Aug 1999 . 10401007 . 10.1093/hmg/8.8.1571 .
• Zito I, Thiselton DL, Gorin MB, Stout JT, Plant C, Bird AC, Bhattacharya SS, Hardcastle AJ . Identification of novel RPGR (retinitis pigmentosa GTPase regulator) mutations in a subset of X-linked retinitis pigmentosa families segregating with the RP3 locus . Human Genetics . 105 . 1–2 . 57–62 . 1999 . 10480356 . 10.1007/s004390051064 .
• Miano MG, Testa F, Strazzullo M, Trujillo M, De Bernardo C, Grammatico B, Simonelli F, Mangino M, Torrente I, Ruberto G, Beneyto M, Antinolo G, Rinaldi E, Danesino C, Ventruto V, D'Urso M, Ayuso C, Baiget M, Ciccodicola A . Mutation analysis of the RPGR gene reveals novel mutations in south European patients with X-linked retinitis pigmentosa . European Journal of Human Genetics . 7 . 6 . 687–94 . Sep 1999 . 10482958 . 10.1038/sj.ejhg.5200352 . free .
• Hong DH, Pawlyk BS, Shang J, Sandberg MA, Berson EL, Li T . A retinitis pigmentosa GTPase regulator (RPGR)-deficient mouse model for X-linked retinitis pigmentosa (RP3) . Proceedings of the National Academy of Sciences of the United States of America . 97 . 7 . 3649–54 . Mar 2000 . 10725384 . 16294 . 10.1073/pnas.060037497 . free .
• Zito I, Gorin MB, Plant C, Bird AC, Bhattacharya SS, Hardcastle AJ . Novel mutations of the RPGR gene in RP3 families . Human Mutation . 15 . 4 . 386 . Apr 2000 . 10737996 . 10.1002/(SICI)1098-1004(200004)15:4<386::AID-HUMU23>3.0.CO;2-4 . free .
• Rao KN, Li L, Anand M, Khanna H . Ablation of retinal ciliopathy protein RPGR results in altered photoreceptor ciliary composition . Scientific Reports . 5 . 11137 . 2015 . 26068394 . 10.1038/srep11137 . 4463945. 2015NatSR...511137R .

Notes and References

1. Meindl A, Dry K, Herrmann K, Manson F, Ciccodicola A, Edgar A, Carvalho MR, Achatz H, Hellebrand H, Lennon A, Migliaccio C, Porter K, Zrenner E, Bird A, Jay M, Lorenz B, Wittwer B, D'Urso M, Meitinger T, Wright A . A gene (RPGR) with homology to the RCC1 guanine nucleotide exchange factor is mutated in X-linked retinitis pigmentosa (RP3) . Nature Genetics . 13 . 1 . 35–42 . May 1996 . 8673101 . 10.1038/ng0596-35 . 31695757 .
2. Roepman R, van Duijnhoven G, Rosenberg T, Pinckers AJ, Bleeker-Wagemakers LM, Bergen AA, Post J, Beck A, Reinhardt R, Ropers HH, Cremers FP, Berger W . Positional cloning of the gene for X-linked retinitis pigmentosa 3: homology with the guanine-nucleotide-exchange factor RCC1 . Human Molecular Genetics . 5 . 7 . 1035–41 . Jul 1996 . 8817343 . 10.1093/hmg/5.7.1035 . free . 2066/22748 . free .
3. Murga-Zamalloa CA, Atkins SJ, Peranen J, Swaroop A, Khanna H . Interaction of retinitis pigmentosa GTPase regulator (RPGR) with RAB8A GTPase: implications for cilia dysfunction and photoreceptor degeneration . Human Molecular Genetics . 19 . 18 . 3591–8 . Sep 2010 . 20631154 . 10.1093/hmg/ddq275 . 2928130.
4. Web site: Entrez Gene: RPGR retinitis pigmentosa GTPase regulator.
5. Khanna H . Photoreceptor Sensory Cilium: Traversing the Ciliary Gate . Cells . 4 . 4 . 674–86 . October 2015 . 26501325 . 4695852 . 10.3390/cells4040674 . free .
6. Churchill JD, Bowne SJ, Sullivan LS, Lewis RA, Wheaton DK, Birch DG, Branham KE, Heckenlively JR, Daiger SP . 6 . Mutations in the X-linked retinitis pigmentosa genes RPGR and RP2 found in 8.5% of families with a provisional diagnosis of autosomal dominant retinitis pigmentosa . Investigative Ophthalmology & Visual Science . 54 . 2 . 1411–6 . February 2013 . 23372056 . 3597192 . 10.1167/iovs.12-11541 .
7. Glomset JA, Farnsworth CC . Role of protein modification reactions in programming interactions between ras-related GTPases and cell membranes . Annual Review of Cell Biology . 10 . 181–205 . 1994 . 7888176 . 10.1146/annurev.cb.10.110194.001145 .
8. Rao KN, Zhang W, Li L, Anand M, Khanna H (2016b) Prenylated retinal ciliopathy protein RPGR interacts with PDE6delta and regulates ciliary localization of Joubert syndrome-associated protein INPP5E. Hum Mol Genet 25(20):4533–4545
9. Linari M, Ueffing M, Manson F, Wright A, Meitinger T, Becker J . The retinitis pigmentosa GTPase regulator, RPGR, interacts with the delta subunit of rod cyclic GMP phosphodiesterase . Proceedings of the National Academy of Sciences of the United States of America . 96 . 4 . 1315–20 . Feb 1999 . 9990021 . 15460 . 10.1073/pnas.96.4.1315 . 1999PNAS...96.1315L . free .
10. Murga-Zamalloa CA, Desai NJ, Hildebrandt F, Khanna H . Interaction of ciliary disease protein retinitis pigmentosa GTPase regulator with nephronophthisis-associated proteins in mammalian retinas . Molecular Vision . 16 . 1373–81 . July 2010 . 20664800 . 2905641.
11. Roepman R, Bernoud-Hubac N, Schick DE, Maugeri A, Berger W, Ropers HH, Cremers FP, Ferreira PA . The retinitis pigmentosa GTPase regulator (RPGR) interacts with novel transport-like proteins in the outer segments of rod photoreceptors . Human Molecular Genetics . 9 . 14 . 2095–105 . Sep 2000 . 10958648 . 10.1093/hmg/9.14.2095 . free .
12. Rao KN, Zhang W, Li L, Ronquillo C, Baehr W, Khanna H . Ciliopathy-associated protein CEP290 modifies the severity of retinal degeneration due to loss of RPGR . Human Molecular Genetics . 25 . 10 . 2005–2012 . May 2016 . 26936822 . 5062589 . 10.1093/hmg/ddw075 .
13. Wang J, Deretic D . Molecular complexes that direct rhodopsin transport to primary cilia . Progress in Retinal and Eye Research . 38 . 1–19 . January 2014 . 24135424 . 10.1016/j.preteyeres.2013.08.004 . 3883129 .
14. Moritz OL, Tam BM, Hurd LL, Peränen J, Deretic D, Papermaster DS . Mutant rab8 Impairs docking and fusion of rhodopsin-bearing post-Golgi membranes and causes cell death of transgenic Xenopus rods . Molecular Biology of the Cell . 12 . 8 . 2341–51 . August 2001 . 11514620 . 58598 . 10.1091/mbc.12.8.2341 .
15. Ebermann I, Scholl HP, Charbel Issa P, Becirovic E, Lamprecht J, Jurklies B, Millán JM, Aller E, Mitter D, Bolz H . 6 . A novel gene for Usher syndrome type 2: mutations in the long isoform of whirlin are associated with retinitis pigmentosa and sensorineural hearing loss . Human Genetics . 121 . 2 . 203–11 . April 2007 . 17171570 . 10.1007/s00439-006-0304-0 . 22632047 .
16. Sun X, Park JH, Gumerson J, Wu Z, Swaroop A, Qian H, Roll-Mecak A, Li T (2016) Loss of RPGR glutamylation underlies the pathogenic mechanism of retinal dystrophy caused by TTLL5 mutations. Proc Natl Acad Sci U S A 113:E2925–E2934