Evolutionary Characterization of the Retinitis Pigmentosa GTPase Regulator Gene

Overview

Journal Invest Ophthalmol Vis Sci

Specialty Ophthalmology

Date 2015 Oct 3

PMID 26431479

Citations 10

Authors

Rakesh Kotapati Raghupathy

Philippe Gautier

Dinesh C Soares

Alan F Wright

Xinhua Shu

Affiliations

Soon will be listed here.

Abstract

Purpose: The evolutionary conservation of the retinitis pigmentosa GTPase regulator (RPGR) gene was examined across vertebrate and invertebrate lineages to elucidate its function.

Methods: Orthologous RPGR sequences from vertebrates and invertebrates were selected. Multiple sequence alignments, phylogenetic analyses, synteny, and gene structure comparisons were carried out. Expression of the alternatively spliced constitutive (RPGR(const) or RPGR(ex1-19)) and RPGR(ORF15) isoforms was examined in developing and adult zebrafish.

Results: Phylogenetic analyses and syntenic relationships were consistent with the selected sequences being true orthologues, although whole genome duplications in teleost fish resulted in a more complex picture. The splice form RPGR(const) was present in all vertebrate and invertebrate species but the defining carboxyl (C)-terminal exon of RPGR(ORF15) was absent from all invertebrates. The regulator of chromosome condensation (RCC1)-like domain adopts a seven-bladed β-propeller structure, which was present in both major splice forms and strongly conserved across evolution. The repetitive acidic region of RPGR(ORF15) showed a high rate of in-frame deletions/insertions across nine primate species, compared with flanking sequences, consistent with an unstable and rapidly evolving region. In zebrafish, RPGR(const) transcripts were most strongly expressed in early development, while the RPGR(ORF15) isoform showed highest expression in adult eye.

Conclusions: The regulator of chromosome condensation 1-like domain of RPGR was conserved in vertebrates and invertebrates, but RPGR(ORF15) was unique to vertebrates, consistent with a proposed role in the ciliary-based transport of cargoes such as rhodopsin, which is ∼10 times more abundant in vertebrate than invertebrate photoreceptors. The repetitive acidic region of RPGR(ORF15) shows a rapid rate of evolution, consistent with a mutation "hot spot."

Citing Articles

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References

Goldsmith T . Photoreceptor processes: some problems and perspectives. J Exp Zool. 1975; 194(1):89-101. DOI: 10.1002/jez.1401940107. View

Meindl A, Dry K, Herrmann K, Manson F, Ciccodicola A, Edgar A . A gene (RPGR) with homology to the RCC1 guanine nucleotide exchange factor is mutated in X-linked retinitis pigmentosa (RP3). Nat Genet. 1996; 13(1):35-42. DOI: 10.1038/ng0596-35. View

Shu X, Zeng Z, Eckmiller M, Gautier P, Vlachantoni D, Manson F . Developmental and tissue expression of Xenopus laevis RPGR. Invest Ophthalmol Vis Sci. 2005; 47(1):348-56. DOI: 10.1167/iovs.05-0858. View

Humphries M, Rancourt D, Farrar G, Kenna P, Hazel M, Bush R . Retinopathy induced in mice by targeted disruption of the rhodopsin gene. Nat Genet. 1997; 15(2):216-9. DOI: 10.1038/ng0297-216. View

Megaw R, Soares D, Wright A . RPGR: Its role in photoreceptor physiology, human disease, and future therapies. Exp Eye Res. 2015; 138:32-41. PMC: 4553903. DOI: 10.1016/j.exer.2015.06.007. View

Shu X, McDowall E, Brown A, Wright A . The human retinitis pigmentosa GTPase regulator gene variant database. Hum Mutat. 2008; 29(5):605-8. DOI: 10.1002/humu.20733. View

Labokha A, Gradmann S, Frey S, Hulsmann B, Urlaub H, Baldus M . Systematic analysis of barrier-forming FG hydrogels from Xenopus nuclear pore complexes. EMBO J. 2012; 32(2):204-18. PMC: 3553378. DOI: 10.1038/emboj.2012.302. View

Tamura K, Stecher G, Peterson D, Filipski A, Kumar S . MEGA6: Molecular Evolutionary Genetics Analysis version 6.0. Mol Biol Evol. 2013; 30(12):2725-9. PMC: 3840312. DOI: 10.1093/molbev/mst197. View

Arendt D, Tessmar-Raible K, Snyman H, Dorresteijn A, Wittbrodt J . Ciliary photoreceptors with a vertebrate-type opsin in an invertebrate brain. Science. 2004; 306(5697):869-71. DOI: 10.1126/science.1099955. View

10.

Burge C, Karlin S . Prediction of complete gene structures in human genomic DNA. J Mol Biol. 1997; 268(1):78-94. DOI: 10.1006/jmbi.1997.0951. View

11.

Kozmik Z, Ruzickova J, Jonasova K, Matsumoto Y, Vopalensky P, Kozmikova I . Assembly of the cnidarian camera-type eye from vertebrate-like components. Proc Natl Acad Sci U S A. 2008; 105(26):8989-93. PMC: 2449352. DOI: 10.1073/pnas.0800388105. View

12.

Shu X, Black G, Rice J, Hart-Holden N, Jones A, OGrady A . RPGR mutation analysis and disease: an update. Hum Mutat. 2006; 28(4):322-8. DOI: 10.1002/humu.20461. View

13.

Shu X, Fry A, Tulloch B, Manson F, Crabb J, Khanna H . RPGR ORF15 isoform co-localizes with RPGRIP1 at centrioles and basal bodies and interacts with nucleophosmin. Hum Mol Genet. 2005; 14(9):1183-97. DOI: 10.1093/hmg/ddi129. View

14.

Watzlich D, Vetter I, Gotthardt K, Miertzschke M, Chen Y, Wittinghofer A . The interplay between RPGR, PDEδ and Arl2/3 regulate the ciliary targeting of farnesylated cargo. EMBO Rep. 2013; 14(5):465-72. PMC: 3642377. DOI: 10.1038/embor.2013.37. View

15.

Hong D, Pawlyk B, Sokolov M, Strissel K, Yang J, Tulloch B . RPGR isoforms in photoreceptor connecting cilia and the transitional zone of motile cilia. Invest Ophthalmol Vis Sci. 2003; 44(6):2413-21. DOI: 10.1167/iovs.02-1206. View

16.

Wright R, Hong D, Perkins B . RpgrORF15 connects to the usher protein network through direct interactions with multiple whirlin isoforms. Invest Ophthalmol Vis Sci. 2012; 53(3):1519-29. PMC: 3339914. DOI: 10.1167/iovs.11-8845. View

17.

Uversky V, Oldfield C, Dunker A . Intrinsically disordered proteins in human diseases: introducing the D2 concept. Annu Rev Biophys. 2008; 37:215-46. DOI: 10.1146/annurev.biophys.37.032807.125924. View

18.

Thompson D, Khan N, Othman M, Chang B, Jia L, Grahek G . Rd9 is a naturally occurring mouse model of a common form of retinitis pigmentosa caused by mutations in RPGR-ORF15. PLoS One. 2012; 7(5):e35865. PMC: 3341386. DOI: 10.1371/journal.pone.0035865. View

19.

Higgins D, Thompson J, Gibson T . Using CLUSTAL for multiple sequence alignments. Methods Enzymol. 1996; 266:383-402. DOI: 10.1016/s0076-6879(96)66024-8. View

20.

Sharon D, Sandberg M, Rabe V, Stillberger M, Dryja T, Berson E . RP2 and RPGR mutations and clinical correlations in patients with X-linked retinitis pigmentosa. Am J Hum Genet. 2003; 73(5):1131-46. PMC: 1180492. DOI: 10.1086/379379. View