4qam

Structural highlights

Disease

[RPGR_HUMAN] Primary ciliary dyskinesia;Achromatopsia;Primary ciliary dyskinesia - retinitis pigmentosa;Cone rod dystrophy;Retinitis pigmentosa. Defects in RPGR are the cause of retinitis pigmentosa type 3 (RP3) [MIM:300029]; also known as X-linked retinitis pigmentosa 3 (XLRP-3) or retinitis pigmentosa type 15 (RP15). A X-linked retinal dystrophy belonging to the group of pigmentary retinopathies. RP is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. In RP3, affected males have a severe phenotype, and carrier females show a wide spectrum of clinical features ranging from completely asymptomatic to severe retinitis pigmentosa. Heterozygous women can manifest a form of choroidoretinal degeneration which is distinguished from other types by the absence of visual defects in the presence of a brilliant, scintillating, golden-hued, patchy appearance most striking around the macula, called a tapetal-like retinal reflex.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]} Defects in RPGR are the cause of retinitis pigmentosa and sinorespiratory infections with or without deafness (RPDSI) [MIM:300455]. A disease characterized by the association primary ciliary dyskinesia features with retinitis pigmentosa. Some patients also manifest deafness.^{[15] [16]} Defects in RPGR are the cause of cone-rod dystrophy X-linked type 1 (CORDX1) [MIM:304020]; also known as cone dystrophy 1 (CO1). CORDs are inherited retinal dystrophies belonging to the group of pigmentary retinopathies. CORDs are characterized by retinal pigment deposits visible on fundus examination, predominantly in the macular region, and initial loss of cone photoreceptors followed by rod degeneration. This leads to decreased visual acuity and sensitivity in the central visual field, followed by loss of peripheral vision. Severe loss of vision occurs earlier than in retinitis pigmentosa. In CORDX1 the degree of rod-photoreceptor involvement can be variable, with degeneration increasing as the disease progresses. Affected individuals (essentially all of whom are males) present with decreased visual acuity, myopia, photophobia, abnormal color vision, full peripheral visual fields, decreased photopic electroretinographic responses, and granularity of the macular retinal pigment epithelium. Although penetrance appears to be nearly 100%, there is variable expressivity with respect to age at onset and severity of symptoms.^[17] Defects in RPGR are a cause of macular degeneration X-linked atrophic (MDXLA) [MIM:300834]. MDXLA is an ocular disorder characterized by macular atrophy causing progressive loss of visual acuity with minimal peripheral visual impairment. Some patients manifest extensive macular degeneration plus peripheral loss of retinal pigment epithelium and choriocapillaries. Full-field electroretinograms (ERGs) show normal cone and rod responses in some affected males despite advanced macular degeneration.^[18] [RPGR1_HUMAN] Leber congenital amaurosis;Meckel syndrome;Cone rod dystrophy. The disease is caused by mutations affecting the gene represented in this entry.^{[19] [20]} The disease is caused by mutations affecting the gene represented in this entry.^{[21] [22]} Heterozygous non-synonymous variants of RPGRIP1 may cause or increase the susceptibility to various forms of glaucoma, a genetically heterogeneous disorder. It is the second cause of blindness worldwide owing to the progressive degeneration of retinal ganglion neurons.

Function

[RPGR_HUMAN] Could be a guanine-nucleotide releasing factor. Plays a role in ciliogenesis. Probably regulates cilia formation by regulating actin stress filaments and cell contractility. Plays an important role in photoreceptor integrity. May play a critical role in spermatogenesis and in intraflagellar transport processes (By similarity). May be involved in microtubule organization and regulation of transport in primary cilia.^[23] [RPGR1_HUMAN] Essential for RPGR function and is also required for normal disk morphogenesis (By similarity).

References

1. ↑ 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. Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1315-20. PMID:9990021
2. ↑ 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). Nat Genet. 1996 May;13(1):35-42. PMID:8673101 doi:10.1038/ng0596-35
3. ↑ 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. Hum Mol Genet. 1996 Jul;5(7):1035-41. PMID:8817343
4. ↑ Vervoort R, Lennon A, Bird AC, Tulloch B, Axton R, Miano MG, Meindl A, Meitinger T, Ciccodicola A, Wright AF. Mutational hot spot within a new RPGR exon in X-linked retinitis pigmentosa. Nat Genet. 2000 Aug;25(4):462-6. PMID:10932196 doi:10.1038/78182
5. ↑ Mears AJ, Hiriyanna S, Vervoort R, Yashar B, Gieser L, Fahrner S, Daiger SP, Heckenlively JR, Sieving PA, Wright AF, Swaroop A. Remapping of the RP15 locus for X-linked cone-rod degeneration to Xp11.4-p21.1, and identification of a de novo insertion in the RPGR exon ORF15. Am J Hum Genet. 2000 Oct;67(4):1000-3. Epub 2000 Sep 1. PMID:10970770 doi:S0002-9297(07)63294-7
6. ↑ Buraczynska M, Wu W, Fujita R, Buraczynska K, Phelps E, Andreasson 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. Am J Hum Genet. 1997 Dec;61(6):1287-92. PMID:9399904 doi:S0002-9297(07)60229-8
7. ↑ 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. 1998 Dec;105(12):2286-96. PMID:9855162 doi:S0161-6420(98)91231-3
8. ↑ 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. Eur J Hum Genet. 1999 Sep;7(6):687-94. PMID:10482958 doi:10.1038/sj.ejhg.5200352
9. ↑ Zito I, Gorin MB, Plant C, Bird AC, Bhattacharya SS, Hardcastle AJ. Novel mutations of the RPGR gene in RP3 families. Hum Mutat. 2000 Apr;15(4):386. PMID:10737996 doi:<386::AID-HUMU23>3.0.CO;2-4 10.1002/(SICI)1098-1004(200004)15:4<386::AID-HUMU23>3.0.CO;2-4
10. ↑ Sharon D, Bruns GA, McGee TL, Sandberg MA, Berson EL, Dryja TP. X-linked retinitis pigmentosa: mutation spectrum of the RPGR and RP2 genes and correlation with visual function. Invest Ophthalmol Vis Sci. 2000 Aug;41(9):2712-21. PMID:10937588
11. ↑ Guevara-Fujita M, Fahrner S, Buraczynska K, Cook J, Wheaton D, Cortes F, Vicencio C, Pena M, Fishman G, Mintz-Hittner H, Birch D, Hoffman D, Mears A, Fujita R, Swaroop A. Five novel RPGR mutations in families with X-linked retinitis pigmentosa. Hum Mutat. 2001 Feb;17(2):151. PMID:11180598 doi:<151::AID-HUMU7>3.0.CO;2-W 10.1002/1098-1004(200102)17:2<151::AID-HUMU7>3.0.CO;2-W
12. ↑ Breuer DK, Yashar BM, Filippova E, Hiriyanna S, Lyons RH, Mears AJ, Asaye B, Acar C, Vervoort R, Wright AF, Musarella MA, Wheeler P, MacDonald I, Iannaccone A, Birch D, Hoffman DR, Fishman GA, Heckenlively JR, Jacobson SG, Sieving PA, Swaroop A. A comprehensive mutation analysis of RP2 and RPGR in a North American cohort of families with X-linked retinitis pigmentosa. Am J Hum Genet. 2002 Jun;70(6):1545-54. Epub 2002 Apr 30. PMID:11992260 doi:10.1086/340848
13. ↑ Sharon D, Sandberg MA, Rabe VW, Stillberger M, Dryja TP, Berson EL. RP2 and RPGR mutations and clinical correlations in patients with X-linked retinitis pigmentosa. Am J Hum Genet. 2003 Nov;73(5):1131-46. Epub 2003 Oct 16. PMID:14564670 doi:S0002-9297(07)61975-2
14. ↑ Bader I, Brandau O, Achatz H, Apfelstedt-Sylla E, Hergersberg M, Lorenz B, Wissinger B, Wittwer B, Rudolph G, Meindl A, Meitinger T. X-linked retinitis pigmentosa: RPGR mutations in most families with definite X linkage and clustering of mutations in a short sequence stretch of exon ORF15. Invest Ophthalmol Vis Sci. 2003 Apr;44(4):1458-63. PMID:12657579
15. ↑ Zito I, Downes SM, Patel RJ, Cheetham ME, Ebenezer ND, Jenkins SA, Bhattacharya SS, Webster AR, Holder GE, Bird AC, Bamiou DE, Hardcastle AJ. RPGR mutation associated with retinitis pigmentosa, impaired hearing, and sinorespiratory infections. J Med Genet. 2003 Aug;40(8):609-15. PMID:12920075
16. ↑ Iannaccone A, Breuer DK, Wang XF, Kuo SF, Normando EM, Filippova E, Baldi A, Hiriyanna S, MacDonald CB, Baldi F, Cosgrove D, Morton CC, Swaroop A, Jablonski MM. Clinical and immunohistochemical evidence for an X linked retinitis pigmentosa syndrome with recurrent infections and hearing loss in association with an RPGR mutation. J Med Genet. 2003 Nov;40(11):e118. PMID:14627685
17. ↑ Demirci FY, Rigatti BW, Wen G, Radak AL, Mah TS, Baic CL, Traboulsi EI, Alitalo T, Ramser J, Gorin MB. X-linked cone-rod dystrophy (locus COD1): identification of mutations in RPGR exon ORF15. Am J Hum Genet. 2002 Apr;70(4):1049-53. Epub 2002 Feb 20. PMID:11857109 doi:S0002-9297(07)60315-2
18. ↑ Ayyagari R, Demirci FY, Liu J, Bingham EL, Stringham H, Kakuk LE, Boehnke M, Gorin MB, Richards JE, Sieving PA. X-linked recessive atrophic macular degeneration from RPGR mutation. Genomics. 2002 Aug;80(2):166-71. PMID:12160730
19. ↑ Gerber S, Perrault I, Hanein S, Barbet F, Ducroq D, Ghazi I, Martin-Coignard D, Leowski C, Homfray T, Dufier JL, Munnich A, Kaplan J, Rozet JM. Complete exon-intron structure of the RPGR-interacting protein (RPGRIP1) gene allows the identification of mutations underlying Leber congenital amaurosis. Eur J Hum Genet. 2001 Aug;9(8):561-71. PMID:11528500 doi:http://dx.doi.org/10.1038/sj.ejhg.5200689
20. ↑ Seong MW, Kim SY, Yu YS, Hwang JM, Kim JY, Park SS. Molecular characterization of Leber congenital amaurosis in Koreans. Mol Vis. 2008 Aug 4;14:1429-36. PMID:18682808
21. ↑ 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. Hum Mol Genet. 2000 Sep 1;9(14):2095-105. PMID:10958648
22. ↑ Hameed A, Abid A, Aziz A, Ismail M, Mehdi SQ, Khaliq S. Evidence of RPGRIP1 gene mutations associated with recessive cone-rod dystrophy. J Med Genet. 2003 Aug;40(8):616-9. PMID:12920076
23. ↑ Gakovic M, Shu X, Kasioulis I, Carpanini S, Moraga I, Wright AF. The role of RPGR in cilia formation and actin stability. Hum Mol Genet. 2011 Dec 15;20(24):4840-50. doi: 10.1093/hmg/ddr423. Epub 2011 Sep, 20. PMID:21933838 doi:10.1093/hmg/ddr423
24. ↑ Remans K, Burger M, Vetter IR, Wittinghofer A. C2 domains as protein-protein interaction modules in the ciliary transition zone. Cell Rep. 2014 Jul 10;8(1):1-9. doi: 10.1016/j.celrep.2014.05.049. Epub 2014 Jun , 26. PMID:24981858 doi:http://dx.doi.org/10.1016/j.celrep.2014.05.049