Retinal Degenerative Diseases pp 105-114

Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 664)

Multiprotein Complexes of Retinitis Pigmentosa GTPase Regulator (RPGR), a Ciliary Protein Mutated in X-Linked Retinitis Pigmentosa (XLRP)

  • Carlos Murga-Zamalloa
  • Anand Swaroop
  • Hemant Khanna


Mutations in Retinitis Pigmentosa GTPase Regulator (RPGR) are a frequent cause of X-linked Retinitis Pigmentosa (XLRP). The RPGR gene undergoes extensive alternative splicing and encodes for distinct protein isoforms in the retina. Extensive studies using isoform-specific antibodies and mouse mutants have revealed that RPGR predominantly localizes to the transition zone to primary cilia and associates with selected ciliary and microtubule-associated assemblies in photoreceptors. In this chapter, we have summarized recent advances on understanding the role of RPGR in photoreceptor protein trafficking. We also provide new evidence that suggests the existence of discrete RPGR multiprotein complexes in photoreceptors. Piecing together the RPGR-interactome in different subcellular compartments should provide critical insights into the role of alternative RPGR isoforms in associated orphan and syndromic retinal degenerative diseases.


  1. Ayyagari R, Demirci FY, Liu J et al (2002) X-linked recessive atrophic macular degeneration from RPGR mutation. Genomics 80(2):166–171CrossRefPubMedGoogle Scholar
  2. Badano JL, Mitsuma N, Beales PL et al (2006) The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet 7:125–148CrossRefPubMedGoogle Scholar
  3. Bartolini F, Bhamidipati A, Thomas S et al (2002) Functional overlap between retinitis pigmentosa 2 protein and the tubulin-specific chaperone cofactor C. J Biol Chem 277(17):14629–14634CrossRefPubMedGoogle Scholar
  4. Beltran WA, Hammond P, Acland GM et al (2006) A frameshift mutation in RPGR exon ORF15 causes photoreceptor degeneration and inner retina remodeling in a model of X-linked retinitis pigmentosa. Invest Ophthalmol Vis Sci 47(4):1669–1681CrossRefPubMedGoogle Scholar
  5. Besharse JC (1986) The Retina: a model for cell biological studies Part I. Academic, New York, pp 297–352Google Scholar
  6. Besharse JC, Baker SA, Luby-Phelps K et al (2003) Photoreceptor intersegmental transport and retinal degeneration: a conserved pathway common to motile and sensory cilia. Adv Exp Med Biol 533:157–164PubMedGoogle Scholar
  7. Bird AC (1975) X-linked retinitis pigmentosa. Br J Ophthalmol 59(4):177–199CrossRefPubMedGoogle Scholar
  8. Bird AC (1987) Clinical investigation of retinitis pigmentosa. Prog Clin Biol Res 247:3–20PubMedGoogle Scholar
  9. Bok D, Young RW (1972) The renewal of diffusely distributed protein in the outer segments of rods and cones. Vision Res 12(2):161–168CrossRefPubMedGoogle Scholar
  10. Boylan JP, Wright AF (2000) Identification of a novel protein interacting with RPGR. Hum Mol Genet 9(14):2085–2093CrossRefPubMedGoogle Scholar
  11. Breuer DK, Yashar BM, Filippova E et al (2002) A comprehensive mutation analysis of RP2 and RPGR in a North American cohort of families with X-linked retinitis pigmentosa. Am J Hum Genet 70(6):1545–1554CrossRefPubMedGoogle Scholar
  12. Buraczynska M, Wu W, Fujita R et al (1997) Spectrum of mutations in the RPGR gene that are identified in 20% of families with X-linked retinitis pigmentosa. Am J Hum Genet 61(6):1287–1292CrossRefPubMedGoogle Scholar
  13. Chang B, Khanna H, Hawes N et al (2006) In-frame deletion in a novel centrosomal/ciliary protein CEP290/NPHP6 perturbs its interaction with RPGR and results in early-onset retinal degeneration in the rd16 mouse. Hum Mol Genet 15(11):1847–1857CrossRefPubMedGoogle Scholar
  14. Chapple JP, Hardcastle AJ, Grayson C et al (2000) Mutations in the N-terminus of the X-linked retinitis pigmentosa protein RP2 interfere with the normal targeting of the protein to the plasma membrane. Hum Mol Genet 9(13):1919–1926CrossRefPubMedGoogle Scholar
  15. Davenport JR, Yoder BK (2005) An incredible decade for the primary cilium: a look at a once-forgotten organelle. Am J Physiol Renal Physiol 289(6):F1159–F1169CrossRefPubMedGoogle Scholar
  16. Demirci FY, Rigatti BW, Mah TS et al (2006) A novel RPGR exon ORF15 mutation in a family with X-linked retinitis pigmentosa and Coats'-like exudative vasculopathy. Am J Ophthalmol 141(1):208–210CrossRefPubMedGoogle Scholar
  17. Demirci FY, Rigatti BW, Wen G et al (2002) X-linked cone-rod dystrophy (locus COD1): identification of mutations in RPGR exon ORF15. Am J Hum Genet 70(4):1049–1053CrossRefPubMedGoogle Scholar
  18. Deretic D, Williams AH, Ransom N et al (2005) Rhodopsin C terminus, the site of mutations causing retinal disease, regulates trafficking by binding to ADP-ribosylation factor 4 (ARF4). Proc Natl Acad Sci USA 102(9):3301–3306CrossRefPubMedGoogle Scholar
  19. Dryja TP, Adams SM, Grimsby JL et al (2001) Null RPGRIP1 alleles in patients with Leber congenital amaurosis. Am J Hum Genet 68(5):1295–1298CrossRefPubMedGoogle Scholar
  20. Fishman GA (1978) Retinitis pigmentosa. Genetic percentages. Arch Ophthalmol 96(5):822–826PubMedGoogle Scholar
  21. Fishman GA, Farber MD, Derlacki DJ (1988) X-linked retinitis pigmentosa. Profile of clinical findings. Arch Ophthalmol 106(3):369–375PubMedGoogle Scholar
  22. Fishman GA, Weinberg AB, McMahon TT (1986) X-linked recessive retinitis pigmentosa. Clinical characteristics of carriers. Arch Ophthalmol 104(9):1329–1335PubMedGoogle Scholar
  23. Fujita R, Bingham E, Forsythe P et al (1996) A recombination outside the BB deletion refines the location of the X linked retinitis pigmentosa locus RP3. Am J Hum Genet 59(1):152–158PubMedGoogle Scholar
  24. Fujita R, Buraczynska M, Gieser L et al (1997) 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. Am J Hum Genet 61(3):571–580CrossRefPubMedGoogle Scholar
  25. Gieser L, Fujita R, Goring HH et al (1998) A novel locus (RP24) for X-linked retinitis pigmentosa maps to Xq26-27. Am J Hum Genet 63(5):1439–1447CrossRefPubMedGoogle Scholar
  26. Grayson C, Bartolini F, Chapple JP (2002) Localization in the human retina of the X-linked retinitis pigmentosa protein RP2, its homologue cofactor C and the RP2 interacting protein Arl3. Hum Mol Genet 11(24):3065–3074CrossRefPubMedGoogle Scholar
  27. Hardcastle AJ, Thiselton DL, Van Maldergem L et al (1999) Mutations in the RP2 gene cause disease in 10% of families with familial X-linked retinitis pigmentosa assessed in this study. Am J Hum Genet 64(4):1210–1215CrossRefPubMedGoogle Scholar
  28. Hardcastle AJ, Thiselton DL, Zito I et al (2000) Evidence for a new locus for X-linked retinitis pigmentosa (RP23). Invest Ophthalmol Vis Sci 41(8):2080–2086PubMedGoogle Scholar
  29. Hartong DT, Berson EL, Dryja TP (2006) Retinitis pigmentosa. Lancet 368(9549):1795–1809CrossRefPubMedGoogle Scholar
  30. He S, Parapuram SK, Hurd TW et al (2008) Retinitis Pigmentosa GTPase Regulator (RPGR) protein isoforms in mammalian retina: insights into X-linked Retinitis Pigmentosa and associated ciliopathies. Vision Res 48(3):366–376CrossRefPubMedGoogle Scholar
  31. Heckenlively JR, Yoser SL, Friedman LH et al (1988) Clinical findings and common symptoms in retinitis pigmentosa. Am J Ophthalmol 105(5):504–511PubMedGoogle Scholar
  32. Hirano T (2006) At the heart of the chromosome: SMC proteins in action. Nat Rev Mol Cell Biol 7(5):311–322CrossRefPubMedGoogle Scholar
  33. Hong DH, Li T (2002) Complex expression pattern of RPGR reveals a role for purine-rich exonic splicing enhancers. Invest Ophthalmol Vis Sci 43(11):3373–3382PubMedGoogle Scholar
  34. Hong DH, Pawlyk BS, Adamian M et al (2004) Dominant, gain-of-function mutant produced by truncation of RPGR. Invest Ophthalmol Vis Sci 45(1):36–41CrossRefPubMedGoogle Scholar
  35. Hong DH, Pawlyk BS, Adamian M et al (2005) A single, abbreviated RPGR-ORF15 variant reconstitutes RPGR function in vivo. Invest Ophthalmol Vis Sci 46(2):435–441CrossRefPubMedGoogle Scholar
  36. Hong DH, Pawlyk BS, Shang J (2000) A retinitis pigmentosa GTPase regulator (RPGR)-deficient mouse model for X-linked retinitis pigmentosa (RP3). Proc Natl Acad Sci USA 97(7):3649–3654CrossRefPubMedGoogle Scholar
  37. Hong DH, Pawlyk B, Sokolov M et al (2003) RPGR isoforms in photoreceptor connecting cilia and the transitional zone of motile cilia. Invest Ophthalmol Vis Sci 44(6):2413–2421CrossRefPubMedGoogle Scholar
  38. Hong DH, Yue G, Adamian M et al (2001) Retinitis pigmentosa GTPase regulator (RPGRr)-interacting protein is stably associated with the photoreceptor ciliary axoneme and anchors RPGR to the connecting cilium. J Biol Chem 276(15):12091–12099CrossRefPubMedGoogle Scholar
  39. Hunter DG, Fishman GA, Kretzer FL (1988) Abnormal axonemes in X-linked retinitis pigmentosa. Arch Ophthalmol 106(3):362–368PubMedGoogle Scholar
  40. Iannaccone A, Wang X, Jablonski MM et al (2004) Increasing evidence for syndromic phenotypes associated with RPGR mutations. Am J Ophthalmol 137(4):785–786 author reply 786PubMedGoogle Scholar
  41. Insinna C, Besharse JC (2008) Intraflagellar transport and the sensory outer segment of vertebrate photoreceptors. Dev Dyn 237(8):1982–1992CrossRefPubMedGoogle Scholar
  42. Kahn RA, Volpicelli-Daley L, Bowzard B et al (2005) Arf family GTPases: roles in membrane traffic and microtubule dynamics. Biochem Soc Trans 33(Pt 6):1269–1272PubMedGoogle Scholar
  43. Khanna H, Hurd TW, Lillo C et al (2005) RPGR-ORF15, which is mutated in retinitis pigmentosa, associates with SMC1, SMC3, and microtubule transport proteins. J Biol Chem 280(39):33580–33587CrossRefPubMedGoogle Scholar
  44. Kirschner R, Rosenberg T, Schultz-Heienbrok R et al (1999) RPGR transcription studies in mouse and human tissues reveal a retina-specific isoform that is disrupted in a patient with X-linked retinitis pigmentosa. Hum Mol Genet 8(8):1571–1578CrossRefPubMedGoogle Scholar
  45. Koenekoop RK, Loyer M, Hand CK et al (2003) Novel RPGR mutations with distinct retinitis pigmentosa phenotypes in French-Canadian families. Am J Ophthalmol 136(4):678–687CrossRefPubMedGoogle Scholar
  46. Kuhnel K, Veltel S, Schlichting I et al (2006) Crystal structure of the human retinitis pigmentosa 2 protein and its interaction with Arl3. Structure 14(2):367–378CrossRefPubMedGoogle Scholar
  47. Linari M, Ueffing M, Manson F et al (1999) The retinitis pigmentosa GTPase regulator, RPGR, interacts with the delta subunit of rod cyclic GMP phosphodiesterase. Proc Natl Acad Sci USA 96(4):1315–1320CrossRefPubMedGoogle Scholar
  48. Liu Q, Tan G, Levenkova N et al (2007) The proteome of the mouse photoreceptor sensory cilium complex. Mol Cell Proteomics 6(8):1299–1317CrossRefPubMedGoogle Scholar
  49. Liu Q, Zuo J, Pierce EA (2004) The retinitis pigmentosa 1 protein is a photoreceptor microtubule-associated protein. J Neurosci 24(29):6427–6436CrossRefPubMedGoogle Scholar
  50. Marszalek JR, Liu X, Roberts EA et al (2000) Genetic evidence for selective transport of opsin and arrestin by kinesin-II in mammalian photoreceptors. Cell 102(2):175–187CrossRefPubMedGoogle Scholar
  51. Mavlyutov TA, Zhao H, Ferreira PA (2002) Species-specific subcellular localization of RPGR and RPGRIP isoforms: implications for the phenotypic variability of congenital retinopathies among species. Hum Mol Genet 11(16):1899–1907CrossRefPubMedGoogle Scholar
  52. McGuire RE, Sullivan LS, Blanton SH et al (1995) X-linked dominant cone-rod degeneration: linkage mapping of a new locus for retinitis pigmentosa (RP 15) to Xp22.13–p22.11. Am J Hum Genet 57(1):87–94PubMedGoogle Scholar
  53. Mears AJ, Gieser L, Yan D et al (1999) Protein-truncation mutations in the RP2 gene in a North American cohort of families with X-linked retinitis pigmentosa. Am J Hum Genet 64(3):897–900CrossRefPubMedGoogle Scholar
  54. Meindl A, Dry K, Herrmann K et al (1996) A gene (RPGR) with homology to the RCC1 guanine nucleotide exchange factor is mutated in X-linked retinitis pigmentosa (RP3). Nat Genet 13(1):35–42CrossRefPubMedGoogle Scholar
  55. Melamud A, Shen GQ, Chung D et al (2006) Mapping a new genetic locus for X linked retinitis pigmentosa to Xq28. J Med Genet 43(6):e27CrossRefPubMedGoogle Scholar
  56. Moore A, Escudier E, Roger G et al (2006) RPGR is mutated in patients with a complex X linked phenotype combining primary ciliary dyskinesia and retinitis pigmentosa. J Med Genet 43(4):326–333CrossRefPubMedGoogle Scholar
  57. Otto EA, Loeys B, Khanna H et al (2005) Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin. Nat Genet 37(3):282–288CrossRefPubMedGoogle Scholar
  58. Pazour GJ, Baker SA, Deane JA et al (2002) The intraflagellar transport protein, IFT88, is essential for vertebrate photoreceptor assembly and maintenance. J Cell Biol 157(1):103–113CrossRefPubMedGoogle Scholar
  59. Pedersen LB, Veland IR, Schroder JM et al (2008) Assembly of primary cilia. Dev Dyn 237(8):1993–2006CrossRefPubMedGoogle Scholar
  60. Renault L, Kuhlmann J, Henkel A et al (2001) Structural basis for guanine nucleotide exchange on Ran by the regulator of chromosome condensation (RCC1). Cell 105(2):245–255CrossRefPubMedGoogle Scholar
  61. Roepman R, van Duijnhoven G, Rosenberg T et al (1996) Positional cloning of the gene for X-linked retinitis pigmentosa 3: homology with the guanine-nucleotide-exchange factor RCC1. Hum Mol Genet 5(7):1035–1041CrossRefPubMedGoogle Scholar
  62. Rosenbaum JL, Cole DG, Diener DR (1999) Intraflagellar transport: the eyes have it. J Cell Biol 144(3):385–388CrossRefPubMedGoogle Scholar
  63. Sayer JA, Otto EA, O’Toole J et al (2006) The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nat Genet 38(6):674–681CrossRefPubMedGoogle Scholar
  64. Schwahn U, Lenzner S, Dong J (1998) Positional cloning of the gene for X-linked retinitis pigmentosa 2. Nat Genet 19(4):327–332CrossRefPubMedGoogle Scholar
  65. Sharon D, Bruns GA, McGee TL et al (2000) X-linked retinitis pigmentosa: mutation spectrum of the RPGR and RP2 genes and correlation with visual function. Invest Ophthalmol Vis Sci 41(9):2712–2721PubMedGoogle Scholar
  66. Sharon D, Sandberg MA, Rabe VW et al (2003) RP2 and RPGR mutations and clinical correlations in patients with X-linked retinitis pigmentosa. Am J Hum Genet 73(5):1131–1146CrossRefPubMedGoogle Scholar
  67. Shu X, Black GC, Rice JM et al (2007) RPGR mutation analysis and disease: an update. Hum Mutat 28(4):322–328CrossRefPubMedGoogle Scholar
  68. Shu X, Fry AM, Tulloch B et al (2005) RPGR ORF15 isoform co-localizes with RPGRIP1 at centrioles and basal bodies and interacts with nucleophosmin. Hum Mol Genet 14(9):1183–1197CrossRefPubMedGoogle Scholar
  69. Sullivan LS, Daiger SP (1996) Inherited retinal degeneration: exceptional genetic and clinical heterogeneity. Mol Med Today 2(9):380–386CrossRefPubMedGoogle Scholar
  70. van Dorp DB, Wright AF, Carothers AD et al (1992) A family with RP3 type of X-linked retinitis pigmentosa: an association with ciliary abnormalities. Hum Genet 88(3):331–334CrossRefPubMedGoogle Scholar
  71. Vervoort R, Lennon A, Bird AC et al (2000) Mutational hot spot within a new RPGR exon in X-linked retinitis pigmentosa. Nat Genet 25(4):462–466CrossRefPubMedGoogle Scholar
  72. Williams DS (2002) Transport to the photoreceptor outer segment by myosin VIIa and kinesin II. Vision Res 42(4):455–462CrossRefPubMedGoogle Scholar
  73. Wright AF, Bhattacharya SS, Aldred MA et al (1991) Genetic localisation of the RP2 type of X linked retinitis pigmentosa in a large kindred. J Med Genet 28(7):453–457CrossRefPubMedGoogle Scholar
  74. Yan D, Swain PK, Breuer D et al (1998) Biochemical characterization and subcellular localization of the mouse retinitis pigmentosa GTPase regulator (mRpgr). J Biol Chem 273(31):19656–19663CrossRefPubMedGoogle Scholar
  75. Yang Z, Peachey NS, Moshfeghi DM et al (2002) Mutations in the RPGR gene cause X-linked cone dystrophy. Hum Mol Genet 11(5):605–611CrossRefPubMedGoogle Scholar
  76. Young RW (1968) Passage of newly formed protein through the connecting cilium of retina rods in the frog. J Ultrastruct Res 23(5):462–473CrossRefPubMedGoogle Scholar
  77. Zhang Q, Acland GM, Wu WX et al (2002) Different RPGR exon ORF15 mutations in Canids provide insights into photoreceptor cell degeneration. Hum Mol Genet 11(9):993–1003CrossRefPubMedGoogle Scholar
  78. Zhang H, Liu XH, Zhang K et al (2004) Photoreceptor cGMP phosphodiesterase delta subunit (PDEdelta) functions as a prenyl-binding protein. J Biol Chem 279(1):407–413CrossRefPubMedGoogle Scholar
  79. Zhao Y, Hong DH, Pawlyk B et al (2003) The retinitis pigmentosa GTPase regulator (RPGR)- interacting protein: subserving RPGR function and participating in disk morphogenesis. Proc Natl Acad Sci USA 100(7):3965–3970CrossRefPubMedGoogle Scholar
  80. Zito I, Downes SM, Patel RJ et al (2003) RPGR mutation associated with retinitis pigmentosa, impaired hearing, and sinorespiratory infections. J Med Genet 40(8):609–615CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Carlos Murga-Zamalloa
    • 1
  • Anand Swaroop
    • 2
  • Hemant Khanna
    • 1
  1. 1.Department of Ophthalmology and Visual SciencesKellogg Eye CenterAnn ArborUSA
  2. 2.Neurobiology-Neurodegeneration and Repair laboratory (N-NRL)National Eye Institute, National Institutes of HealthBethesdaUSA

Personalised recommendations