Retinitis pigmentosa GTPase regulator

X-linked retinitis pigmentosa GTPase regulator is a GTPase-binding protein that in humans is encoded by the RPGR gene.[5][6][7][8] 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.[9]

RPGR
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesRPGR, COD1, CORDX1, CRD, PCDX, RP15, RP3, XLRP3, orf15, Retinitis pigmentosa GTPase regulator
External IDsOMIM: 312610 MGI: 1344037 HomoloGene: 55455 GeneCards: RPGR
Gene location (Human)
Chr.X chromosome (human)[1]
BandXp11.4Start38,269,163 bp[1]
End38,327,564 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

6103

19893

Ensembl

ENSG00000156313

ENSMUSG00000031174

UniProt

Q92834

Q9R0X5

RefSeq (mRNA)

NM_000328
NM_001023582
NM_001034853

RefSeq (protein)
Location (UCSC)Chr X: 38.27 – 38.33 MbChr X: 10.07 – 10.22 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[8]

The two major isoforms are RPGRconst, the default isoform, composed of exons 1-19, and RPGRORF15 which retains part of intron 15 as the terminal exon. ORF15 is the terminal exon of RPGRORF15 and is a mutational hotspot accounting for ~60% of RPGR patients with heterogeneous diseases ranging from XLRP to cone-rod degeneration and macular degeneration.[10] Alternatively, the RPGRconst isoform contains a putative prenylation domain on its C-terminal end[10] which is involved in posttranslational modification and allows membrane-association and protein trafficking.[11] The C-terminal domain of the RPGRconst isoform contains a CTIL motif (812CTIL815) which recruits prenyl-binding protein PDE6D which then shuttles the protein to the connecting cilium.[12]

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.[9]

Interactions

Retinitis pigmentosa GTPase regulator has been shown to interact with PDE6D[13] nephronophthisis (NPHP) proteins[14] and RPGRIP1.[15] Binding to PDE6D has been shown to ensure ciliary localization of the RPGRconst isoform.[16] Additionally, the N-terminal of interacts with a PDE6D interacting proetin, INPP5E (inositol polyphosphatase 5E).[12] INPP5E has been shown to regulates phosphoinositide metabolism and may modulate the phosphoinositide content of photoreceptors.[9]

RPGR has also been shown to preferentially interact with the GDP-bound form of the small GTPase RAB8A.[17] RAB8A is involved in rhodopsin trafficking in primary cilia.[18] The C-terminal domain of RPGRORF15 has been shown to interact with whirlin, a ciliary protein that is mutated in Usher Syndrome.[19] The RPGRORF15 isoform has been shown to be glutamylated on its N-terminus by tubulin-tyrosine ligase-like 5 (TTLL5).[20] It has also been shown that loss of TTLL5 mimics loss of RPGR in the mouse retina.

References
  1. GRCh38: Ensembl release 89: ENSG00000156313 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000031174 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 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 (May 1996). "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. doi:10.1038/ng0596-35. PMID 8673101.
  6. 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 (Jul 1996). "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. doi:10.1093/hmg/5.7.1035. PMID 8817343.
  7. Murga-Zamalloa CA, Atkins SJ, Peranen J, Swaroop A, Khanna H (Sep 2010). "Interaction of retinitis pigmentosa GTPase regulator (RPGR) with RAB8A GTPase: implications for cilia dysfunction and photoreceptor degeneration". Human Molecular Genetics. 19 (18): 3591–8. doi:10.1093/hmg/ddq275. PMC 2928130. PMID 20631154.
  8. "Entrez Gene: RPGR retinitis pigmentosa GTPase regulator".
  9. Khanna H (October 2015). "Photoreceptor Sensory Cilium: Traversing the Ciliary Gate". Cells. 4 (4): 674–86. doi:10.3390/cells4040674. PMC 4695852. PMID 26501325.
  10. Churchill JD, Bowne SJ, Sullivan LS, Lewis RA, Wheaton DK, Birch DG, et al. (February 2013). "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. doi:10.1167/iovs.12-11541. PMC 3597192. PMID 23372056.
  11. Glomset JA, Farnsworth CC (1994). "Role of protein modification reactions in programming interactions between ras-related GTPases and cell membranes". Annual Review of Cell Biology. 10: 181–205. doi:10.1146/annurev.cb.10.110194.001145. PMID 7888176.
  12. 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
  13. Linari M, Ueffing M, Manson F, Wright A, Meitinger T, Becker J (Feb 1999). "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. doi:10.1073/pnas.96.4.1315. PMC 15460. PMID 9990021.
  14. Murga-Zamalloa CA, Desai NJ, Hildebrandt F, Khanna H (July 2010). "Interaction of ciliary disease protein retinitis pigmentosa GTPase regulator with nephronophthisis-associated proteins in mammalian retinas". Molecular Vision. 16: 1373–81. PMC 2905641. PMID 20664800.
  15. Roepman R, Bernoud-Hubac N, Schick DE, Maugeri A, Berger W, Ropers HH, Cremers FP, Ferreira PA (Sep 2000). "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. doi:10.1093/hmg/9.14.2095. PMID 10958648.
  16. Rao KN, Zhang W, Li L, Ronquillo C, Baehr W, Khanna H (May 2016). "Ciliopathy-associated protein CEP290 modifies the severity of retinal degeneration due to loss of RPGR". Human Molecular Genetics. 25 (10): 2005–2012. doi:10.1093/hmg/ddw075. PMC 5062589. PMID 26936822.
  17. Wang J, Deretic D (January 2014). "Molecular complexes that direct rhodopsin transport to primary cilia". Progress in Retinal and Eye Research. 38: 1–19. doi:10.1016/j.preteyeres.2013.08.004. PMC 3883129. PMID 24135424.
  18. Moritz OL, Tam BM, Hurd LL, Peränen J, Deretic D, Papermaster DS (August 2001). "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. doi:10.1091/mbc.12.8.2341. PMC 58598. PMID 11514620.
  19. Ebermann I, Scholl HP, Charbel Issa P, Becirovic E, Lamprecht J, Jurklies B, et al. (April 2007). "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. doi:10.1007/s00439-006-0304-0. PMID 17171570.
  20. 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

Further reading
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