RBCC

Full text data of RP2

RP2 [Confidence: high (present in two of the MS resources)]
Protein XRP2

hRBCD IPI00026627
IPI00026627 XRP2 protein XRP2 protein membrane n/a 1 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 3 2 n/a 2 1 n/a 1 1 not mentioned n/a found at its expected molecular weight found at molecular weight

UniProt O75695
ID XRP2_HUMAN Reviewed; 350 AA.
AC O75695; Q86XJ7; Q9NU67;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 4.
DT 22-JAN-2014, entry version 127.
DE RecName: Full=Protein XRP2;
GN Name=RP2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS RP2 SER-6 DEL AND HIS-118.
RC TISSUE=Brain;
RX PubMed=9697692; DOI=10.1038/1214;
RA Schwahn U., Lenzner S., Dong J., Feil S., Hinzmann B.,
RA van Duijnhoven G., Kirschner R., Hemberger M., Bergen A.A.B.,
RA Rosenberg T., Pinckers A.J.L.G., Fundele R., Rosenthal A.,
RA Cremers F.P.M., Ropers H.-H., Berger W.;
RT "Positional cloning of the gene for X-linked retinitis pigmentosa 2.";
RL Nat. Genet. 19:327-332(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A.,
RA Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G.,
RA Jones M.C., Hurles M.E., Andrews T.D., Scott C.E., Searle S.,
RA Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R.,
RA Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L.,
RA Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A.,
RA Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S.,
RA Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R.,
RA Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M.,
RA Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N.,
RA Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D.,
RA Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W.,
RA Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C.,
RA Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C.,
RA Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J.,
RA Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S.,
RA Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I.,
RA Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L.,
RA Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P.,
RA Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S.,
RA Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A.,
RA Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J.,
RA Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J.,
RA Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S.,
RA de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z.,
RA Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C.,
RA Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W.,
RA Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T.,
RA Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I.,
RA Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N.,
RA Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J.,
RA Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E.,
RA Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S.,
RA Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T.,
RA Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S.,
RA Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L.,
RA Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A.,
RA Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L.,
RA Williams G., Williams L., Williamson A., Williamson H., Wilming L.,
RA Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H.,
RA Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A.,
RA Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A.,
RA Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T.,
RA Gibbs R.A., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Eye, and Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [5]
RP CHARACTERIZATION OF VARIANTS RP2 SER-6 DEL AND HIS-118, MYRISTOYLATION
RP AT GLY-2, PALMITOYLATION AT CYS-3, MUTAGENESIS OF GLY-2 AND CYS-3,
RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=10942419; DOI=10.1093/hmg/9.13.1919;
RA Chapple J.P., Hardcastle A.J., Grayson C., Spackman L.A.,
RA Willison K.R., Cheetham M.E.;
RT "Mutations in the N-terminus of the X-linked retinitis pigmentosa
RT protein RP2 interfere with the normal targeting of the protein to the
RT plasma membrane.";
RL Hum. Mol. Genet. 9:1919-1926(2000).
RN [6]
RP FUNCTION, CHARACTERIZATION OF VARIANTS RP2 SER-6 DEL AND HIS-118, AND
RP INTERACTION WITH ARL3.
RX PubMed=11847227; DOI=10.1074/jbc.M200128200;
RA Bartolini F., Bhamidipati A., Thomas S., Schwahn U., Lewis S.A.,
RA Cowan N.J.;
RT "Functional overlap between retinitis pigmentosa 2 protein and the
RT tubulin-specific chaperone cofactor C.";
RL J. Biol. Chem. 277:14629-14634(2002).
RN [7]
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=12417528; DOI=10.1093/hmg/11.24.3065;
RA Grayson C., Bartolini F., Chapple J.P., Willison K.R., Bhamidipati A.,
RA Lewis S.A., Luthert P.J., Hardcastle A.J., Cowan N.J., Cheetham M.E.;
RT "Localization in the human retina of the X-linked retinitis pigmentosa
RT protein RP2, its homologue cofactor C and the RP2 interacting protein
RT Arl3.";
RL Hum. Mol. Genet. 11:3065-3074(2002).
RN [8]
RP IDENTIFICATION IN A COMPLEX WITH ARL3 AND UNC119.
RX PubMed=18588884; DOI=10.1016/j.febslet.2008.05.053;
RA Veltel S., Kravchenko A., Ismail S., Wittinghofer A.;
RT "Specificity of Arl2/Arl3 signaling is mediated by a ternary Arl3-
RT effector-GAP complex.";
RL FEBS Lett. 582:2501-2507(2008).
RN [9]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=20106869; DOI=10.1093/hmg/ddq012;
RA Evans R.J., Schwarz N., Nagel-Wolfrum K., Wolfrum U., Hardcastle A.J.,
RA Cheetham M.E.;
RT "The retinitis pigmentosa protein RP2 links pericentriolar vesicle
RT transport between the Golgi and the primary cilium.";
RL Hum. Mol. Genet. 19:1358-1367(2010).
RN [10]
RP FUNCTION.
RX PubMed=22085962; DOI=10.1101/gad.173054.111;
RA Wright K.J., Baye L.M., Olivier-Mason A., Mukhopadhyay S., Sang L.,
RA Kwong M., Wang W., Pretorius P.R., Sheffield V.C., Sengupta P.,
RA Slusarski D.C., Jackson P.K.;
RT "An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 to the
RT primary cilium.";
RL Genes Dev. 25:2347-2360(2011).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS), INTERACTION WITH ARL3,
RP CHARACTERIZATION OF VARIANTS RP2 HIS-118 AND GLY-138, AND
RP CHARACTERIZATION OF VARIANT TRP-282.
RX PubMed=16472755; DOI=10.1016/j.str.2005.11.008;
RA Kuehnel K., Veltel S., Schlichting I., Wittinghofer A.;
RT "Crystal structure of the human retinitis pigmentosa 2 protein and its
RT interaction with Arl3.";
RL Structure 14:367-378(2006).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 1-350 OF COMPLEX WITH MOUSE
RP ARL3 AND GTP, FUNCTION, INTERACTION WITH ARL3, TISSUE SPECIFICITY,
RP CHARACTERIZATION OF VARIANTS LEU-118 AND GLY-138, AND MUTAGENESIS OF
RP SER-28; TRP-29; GLN-31; ARG-32; PHE-101; GLN-115; GLN-116; ARG-118;
RP ARG-120 AND PHE-177.
RX PubMed=18376416; DOI=10.1038/nsmb.1396;
RA Veltel S., Gasper R., Eisenacher E., Wittinghofer A.;
RT "The retinitis pigmentosa 2 gene product is a GTPase-activating
RT protein for Arf-like 3.";
RL Nat. Struct. Mol. Biol. 15:373-380(2008).
RN [13]
RP VARIANT RP2 HIS-118.
RX PubMed=10090907; DOI=10.1086/302325;
RA Hardcastle A.J., Thiselton D.L., Van Maldergem L., Saha B.K., Jay M.,
RA Plant C., Taylor R., Bird A.C., Bhattacharya S.;
RT "Mutations in the RP2 gene cause disease in 10% of families with
RT familial X-Linked retinitis pigmentosa assessed in this study.";
RL Am. J. Hum. Genet. 64:1210-1215(1999).
RN [14]
RP VARIANTS RP2 SER-6 DEL AND HIS-118.
RX PubMed=10520237; DOI=10.1076/opge.20.3.161.2278;
RA Rosenberg T., Schwahn U., Feil S., Berger W.;
RT "Genotype-phenotype correlation in X-linked retinitis pigmentosa 2
RT (RP2).";
RL Ophthalmic Genet. 20:161-172(1999).
RN [15]
RP VARIANTS TRP-282 AND TYR-338.
RX PubMed=10862093;
RX DOI=10.1002/1098-1004(200006)15:6<580::AID-HUMU15>3.0.CO;2-3;
RA Thiselton D.L., Zito I., Plant C., Jay M., Hodgson S.V., Bird A.C.,
RA Bhattacharya S.S., Hardcastle A.J.;
RT "Novel frameshift mutations in the RP2 gene and polymorphic
RT variants.";
RL Hum. Mutat. 15:580-580(2000).
RN [16]
RP VARIANT RP2 ARG-253.
RX PubMed=10634633;
RA Wada Y., Nakazawa M., Abe T., Tamai M.;
RT "A new Leu253Arg mutation in the RP2 gene in a Japanese family with X-
RT linked retinitis pigmentosa.";
RL Invest. Ophthalmol. Vis. Sci. 41:290-293(2000).
RN [17]
RP VARIANTS RP2 TYR-86; LEU-95; HIS-118 AND ILE-137 DEL, AND VARIANT
RP TRP-282.
RX PubMed=10937588;
RA Sharon D., Bruns G.A.P., McGee T.L., Sandberg M.A., Berson E.L.,
RA Dryja T.P.;
RT "X-linked retinitis pigmentosa: mutation spectrum of the RPGR and RP2
RT genes and correlation with visual function.";
RL Invest. Ophthalmol. Vis. Sci. 41:2712-2721(2000).
RN [18]
RP VARIANTS RP2 LEU-118 AND GLY-138, AND VARIANT TRP-282.
RX PubMed=11462235; DOI=10.1002/humu.1160;
RA Miano M.G., Testa F., Filippini F., Trujillo M., Conte I., Lanzara C.,
RA Millan J.M., De Bernardo C., Grammatico B., Mangino M., Torrente I.,
RA Carrozzo R., Simonelli F., Rinaldi E., Ventruto V., D'Urso M.,
RA Ayuso C., Ciccodicola A.;
RT "Identification of novel RP2 mutations in a subset of X-linked
RT retinitis pigmentosa families and prediction of new domains.";
RL Hum. Mutat. 18:109-119(2001).
RN [19]
RP VARIANTS RP2 TYR-67; HIS-118; ILE-137 DEL AND PRO-188, AND VARIANT
RP TRP-282.
RX PubMed=11992260; DOI=10.1086/340848;
RA Breuer D.K., Yashar B.M., Filippova E., Hiriyanna S., Lyons R.H.,
RA Mears A.J., Asaye B., Acar C., Vervoort R., Wright A.F.,
RA Musarella M.A., Wheeler P., MacDonald I., Iannaccone A., Birch D.,
RA Hoffman D.R., Fishman G.A., Heckenlively J.R., Jacobson S.G.,
RA Sieving P.A., Swaroop A.;
RT "A comprehensive mutation analysis of RP2 and RPGR in a North American
RT cohort of families with X-linked retinitis pigmentosa.";
RL Am. J. Hum. Genet. 70:1545-1554(2002).
RN [20]
RP VARIANTS RP2 TYR-86; LEU-95; HIS-118 AND ILE-137 DEL, AND VARIANT
RP TRP-282.
RX PubMed=14564670; DOI=10.1086/379379;
RA Sharon D., Sandberg M.A., Rabe V.W., Stillberger M., Dryja T.P.,
RA Berson E.L.;
RT "RP2 and RPGR mutations and clinical correlations in patients with X-
RT linked retinitis pigmentosa.";
RL Am. J. Hum. Genet. 73:1131-1146(2003).
RN [21]
RP VARIANTS RP2 HIS-118 AND CYS-118.
RX PubMed=12657579; DOI=10.1167/iovs.02-0605;
RA Bader I., Brandau O., Achatz H., Apfelstedt-Sylla E., Hergersberg M.,
RA Lorenz B., Wissinger B., Wittwer B., Rudolph G., Meindl A.,
RA Meitinger T.;
RT "X-linked retinitis pigmentosa: RPGR mutations in most families with
RT definite X linkage and clustering of mutations in a short sequence
RT stretch of exon ORF15.";
RL Invest. Ophthalmol. Vis. Sci. 44:1458-1463(2003).
RN [22]
RP VARIANT RP2 TYR-108.
RX PubMed=22334370; DOI=10.1002/humu.22045;
RA Neveling K., Collin R.W., Gilissen C., van Huet R.A., Visser L.,
RA Kwint M.P., Gijsen S.J., Zonneveld M.N., Wieskamp N., de Ligt J.,
RA Siemiatkowska A.M., Hoefsloot L.H., Buckley M.F., Kellner U.,
RA Branham K.E., den Hollander A.I., Hoischen A., Hoyng C.,
RA Klevering B.J., van den Born L.I., Veltman J.A., Cremers F.P.,
RA Scheffer H.;
RT "Next-generation genetic testing for retinitis pigmentosa.";
RL Hum. Mutat. 33:963-972(2012).
CC -!- FUNCTION: Acts as a GTPase-activating protein (GAP) involved in
CC trafficking between the Golgi and the ciliary membrane. Involved
CC in localization of proteins, such as NPHP3, to the cilium membrane
CC by inducing hydrolysis of GTP ARL3, leading to the release of
CC UNC119 (or UNC119B). Acts as a GTPase-activating protein (GAP) for
CC tubulin in concert with tubulin-specific chaperone C, but does not
CC enhance tubulin heterodimerization. Acts as guanine nucleotide
CC dissociation inhibitor towards ADP-ribosylation factor-like
CC proteins.
CC -!- SUBUNIT: Found in a complex with ARL3, RP2 and UNC119 (or
CC UNC119B); RP2 induces hydrolysis of GTP ARL3 in the complex,
CC leading to the release of UNC119 (or UNC119B). Interacts with
CC ARL3; interaction is direct and stimulated with the activated GTP-
CC bound form of ARL3.
CC -!- SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor; Cytoplasmic
CC side. Cell projection, cilium. Note=Detected predominantly to the
CC plasma membrane of rod and cone photoreceptors. Not detected in
CC the nucleus.
CC -!- TISSUE SPECIFICITY: Ubiquitous. Expressed in the rod and cone
CC photoreceptors, extending from the tips of the outer segment (OS)
CC through the inner segment (IS) and outer nuclear layer (ONL) and
CC into the synaptic terminals of the outer plexiform layer (ONL).
CC Also detected in the bipolar, horizontal and amacrine cells in the
CC inner nuclear layer (INL), extending to the inner plexiform layer
CC (IPL) and though the ganglion cell layer (GCL) and into the nerve
CC fiber layer (NFL) (at protein level).
CC -!- PTM: Myristoylated on Gly-2; which may be required for membrane
CC targeting (Probable).
CC -!- PTM: Palmitoylated on Cys-3; which may be required for plasma
CC membrane targeting (Probable). Mutation of Cys-3 targets the
CC protein to internal membranes.
CC -!- DISEASE: Retinitis pigmentosa 2 (RP2) [MIM:312600]: A retinal
CC dystrophy belonging to the group of pigmentary retinopathies.
CC Retinitis pigmentosa is characterized by retinal pigment deposits
CC visible on fundus examination and primary loss of rod
CC photoreceptor cells followed by secondary loss of cone
CC photoreceptors. Patients typically have night vision blindness and
CC loss of midperipheral visual field. As their condition progresses,
CC they lose their far peripheral visual field and eventually central
CC vision as well. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the TBCC family.
CC -!- SIMILARITY: Contains 1 C-CAP/cofactor C-like domain.
CC -!- WEB RESOURCE: Name=Mutations of the RP2 gene; Note=Retina
CC International's Scientific Newsletter;
CC URL="http://www.retina-international.org/files/sci-news/rp2mut.htm";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/RP2";
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DR EMBL; AJ007590; CAA07577.1; -; mRNA.
DR EMBL; AL050307; CAB82030.2; -; Genomic_DNA.
DR EMBL; AL627143; CAB82030.2; JOINED; Genomic_DNA.
DR EMBL; BC043348; AAH43348.1; -; mRNA.
DR EMBL; BC053530; AAH53530.1; -; mRNA.
DR RefSeq; NP_008846.2; NM_006915.2.
DR UniGene; Hs.44766; -.
DR PDB; 2BX6; X-ray; 2.10 A; A=1-350.
DR PDB; 3BH6; X-ray; 2.60 A; B=1-350.
DR PDB; 3BH7; X-ray; 1.90 A; B=1-350.
DR PDBsum; 2BX6; -.
DR PDBsum; 3BH6; -.
DR PDBsum; 3BH7; -.
DR ProteinModelPortal; O75695; -.
DR SMR; O75695; 37-350.
DR DIP; DIP-29024N; -.
DR IntAct; O75695; 1.
DR MINT; MINT-5003911; -.
DR STRING; 9606.ENSP00000218340; -.
DR PhosphoSite; O75695; -.
DR PaxDb; O75695; -.
DR PeptideAtlas; O75695; -.
DR PRIDE; O75695; -.
DR DNASU; 6102; -.
DR Ensembl; ENST00000218340; ENSP00000218340; ENSG00000102218.
DR Ensembl; ENST00000603075; ENSP00000474087; ENSG00000271091.
DR GeneID; 6102; -.
DR KEGG; hsa:6102; -.
DR UCSC; uc004dgw.4; human.
DR CTD; 6102; -.
DR GeneCards; GC0XP046696; -.
DR H-InvDB; HIX0016754; -.
DR HGNC; HGNC:10274; RP2.
DR HPA; HPA000234; -.
DR MIM; 300757; gene.
DR MIM; 312600; phenotype.
DR neXtProt; NX_O75695; -.
DR Orphanet; 791; Retinitis pigmentosa.
DR PharmGKB; PA34641; -.
DR eggNOG; NOG326369; -.
DR HOGENOM; HOG000007790; -.
DR HOVERGEN; HBG054784; -.
DR InParanoid; O75695; -.
DR OMA; QWYYPEL; -.
DR OrthoDB; EOG7ZPNKQ; -.
DR PhylomeDB; O75695; -.
DR EvolutionaryTrace; O75695; -.
DR GeneWiki; RP2_(gene); -.
DR GenomeRNAi; 6102; -.
DR NextBio; 23737; -.
DR PRO; PR:O75695; -.
DR Bgee; O75695; -.
DR CleanEx; HS_RP2; -.
DR Genevestigator; O75695; -.
DR GO; GO:0036064; C:cilium basal body; IDA:MGI.
DR GO; GO:0031410; C:cytoplasmic vesicle; IGI:MGI.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:InterPro.
DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR GO; GO:0005096; F:GTPase activator activity; IDA:UniProtKB.
DR GO; GO:0004550; F:nucleoside diphosphate kinase activity; IEA:InterPro.
DR GO; GO:0051082; F:unfolded protein binding; TAS:ProtInc.
DR GO; GO:0000902; P:cell morphogenesis; IEA:InterPro.
DR GO; GO:0006241; P:CTP biosynthetic process; IEA:InterPro.
DR GO; GO:0007010; P:cytoskeleton organization; IEA:InterPro.
DR GO; GO:0006183; P:GTP biosynthetic process; IEA:InterPro.
DR GO; GO:0006457; P:protein folding; TAS:UniProtKB.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0006228; P:UTP biosynthetic process; IEA:InterPro.
DR GO; GO:0007601; P:visual perception; TAS:ProtInc.
DR Gene3D; 2.160.20.70; -; 1.
DR InterPro; IPR013912; Adenylate_cyclase-assoc_CAP_C.
DR InterPro; IPR017901; C-CAP_CF_C-like.
DR InterPro; IPR016098; CAP/MinC_C.
DR InterPro; IPR006599; CARP_motif.
DR InterPro; IPR001564; Nucleoside_diP_kinase.
DR InterPro; IPR017332; Protein_XRP2.
DR InterPro; IPR012945; Tubulin-bd_cofactor_C_dom.
DR PANTHER; PTHR15440:SF0; PTHR15440:SF0; 1.
DR Pfam; PF07986; TBCC; 1.
DR PIRSF; PIRSF037947; Protein_XRP2_; 1.
DR SMART; SM00673; CARP; 2.
DR SUPFAM; SSF54919; SSF54919; 1.
DR SUPFAM; SSF69340; SSF69340; 1.
DR PROSITE; PS51329; C_CAP_COFACTOR_C; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Cell projection; Cilium;
KW Complete proteome; Disease mutation; GTP-binding; GTPase activation;
KW Lipoprotein; Membrane; Myristate; Nucleotide-binding; Palmitate;
KW Polymorphism; Protein transport; Reference proteome;
KW Retinitis pigmentosa; Transport.
FT INIT_MET 1 1 Removed (Probable).
FT CHAIN 2 350 Protein XRP2.
FT /FTId=PRO_0000080047.
FT DOMAIN 24 179 C-CAP/cofactor C-like.
FT NP_BIND 98 99 GTP.
FT NP_BIND 115 118 GTP.
FT LIPID 2 2 N-myristoyl glycine (Probable).
FT LIPID 3 3 S-palmitoyl cysteine (Probable).
FT VARIANT 6 6 Missing (in RP2; loss of membrane
FT association; enhances interaction with
FT ARL3).
FT /FTId=VAR_008497.
FT VARIANT 67 67 C -> Y (in RP2).
FT /FTId=VAR_018069.
FT VARIANT 86 86 C -> Y (in RP2).
FT /FTId=VAR_018070.
FT VARIANT 95 95 P -> L (in RP2; uncertain pathological
FT significance).
FT /FTId=VAR_018071.
FT VARIANT 108 108 C -> G (in RP2).
FT /FTId=VAR_008498.
FT VARIANT 108 108 C -> Y (in RP2).
FT /FTId=VAR_068353.
FT VARIANT 118 118 R -> C (in RP2).
FT /FTId=VAR_026058.
FT VARIANT 118 118 R -> H (in RP2; reduces affinity for ARL3
FT 800-fold; loss of stimulation of tubulin
FT GTPase activity; no effect on subcellular
FT location).
FT /FTId=VAR_008499.
FT VARIANT 118 118 R -> L (in RP2; dbSNP:rs28933687).
FT /FTId=VAR_018072.
FT VARIANT 137 137 Missing (in RP2).
FT /FTId=VAR_018073.
FT VARIANT 138 138 E -> G (in RP2; reduces affinity for ARL3
FT 150-fold and inhibits the GTP-hydrolysis
FT rate of ARL3).
FT /FTId=VAR_018074.
FT VARIANT 144 144 K -> R (in dbSNP:rs3126141).
FT /FTId=VAR_053961.
FT VARIANT 188 188 L -> P (in RP2).
FT /FTId=VAR_018075.
FT VARIANT 253 253 L -> R (in RP2).
FT /FTId=VAR_008500.
FT VARIANT 282 282 R -> W (might play a role in retinitis
FT pigmentosa 2; reduces affinity for ARL3
FT 3-fold; dbSNP:rs1805147).
FT /FTId=VAR_014535.
FT VARIANT 338 338 D -> Y (in dbSNP:rs1805148).
FT /FTId=VAR_014536.
FT MUTAGEN 2 2 G->A: Loss of membrane association.
FT MUTAGEN 3 3 C->S: Targeting to internal membranes.
FT Loss of targeting to the plasma membrane.
FT MUTAGEN 28 28 S->A: Reduces affinity for mouse ARL3;
FT when associated with A-29.
FT MUTAGEN 29 29 W->A: Reduces affinity for mouse ARL3;
FT when associated with A-28.
FT MUTAGEN 31 31 Q->A: Does not reduce affinity for mouse
FT ARL3; when associated with A-32.
FT MUTAGEN 32 32 R->A: Does not reduce affinity for mouse
FT ARL3; when associated with A-31.
FT MUTAGEN 101 101 F->A: Reduces affinity for mouse ARL3.
FT MUTAGEN 115 115 Q->A: Reduces affinity for mouse ARL3.
FT MUTAGEN 116 116 Q->A: Reduces affinity and GTP-hydrolysis
FT rate for mouse ARL3.
FT MUTAGEN 118 118 R->A: Reduces affinity and GTP-hydrolysis
FT rate for mouse ARL3.
FT MUTAGEN 120 120 R->H: Reduces affinity for mouse ARL3;
FT when associated with S-121.
FT MUTAGEN 121 121 D->S: Reduces affinity for mouse ARL3;
FT when associated with H-120.
FT MUTAGEN 177 177 F->A: Reduces affinity and GTP-hydrolysis
FT rate for mouse ARL3.
FT CONFLICT 168 168 N -> D (in Ref. 1; CAA07577).
FT STRAND 39 44
FT STRAND 49 52
FT STRAND 62 66
FT STRAND 71 74
FT STRAND 81 85
FT STRAND 90 104
FT STRAND 106 121
FT STRAND 123 133
FT STRAND 136 139
FT STRAND 141 147
FT HELIX 155 161
FT STRAND 175 178
FT STRAND 185 188
FT HELIX 195 197
FT HELIX 205 207
FT TURN 216 218
FT STRAND 235 240
FT HELIX 246 259
FT STRAND 263 270
FT HELIX 274 281
FT HELIX 282 287
FT HELIX 289 294
FT STRAND 297 304
FT HELIX 307 318
FT STRAND 324 326
FT HELIX 330 348
SQ SEQUENCE 350 AA; 39641 MW; 3C912B52C53A817E CRC64;
MGCFFSKRRK ADKESRPENE EERPKQYSWD QREKVDPKDY MFSGLKDETV GRLPGTVAGQ
QFLIQDCENC NIYIFDHSAT VTIDDCTNCI IFLGPVKGSV FFRNCRDCKC TLACQQFRVR
DCRKLEVFLC CATQPIIESS SNIKFGCFQW YYPELAFQFK DAGLSIFNNT WSNIHDFTPV
SGELNWSLLP EDAVVQDYVP IPTTEELKAV RVSTEANRSI VPISRGQRQK SSDESCLVVL
FAGDYTIANA RKLIDEMVGK GFFLVQTKEV SMKAEDAQRV FREKAPDFLP LLNKGPVIAL
EFNGDGAVEV CQLIVNEIFN GTKMFVSESK ETASGDVDSF YNFADIQMGI
//

MIM 300757
*RECORD*
*FIELD* NO
300757
*FIELD* TI
*300757 RP2 GENE; RP2
*FIELD* TX

CLONING

By positional cloning in a 5-cM genomic interval linked to retinitis
read morepigmentosa 2 (RP2; 312600), Schwahn et al. (1998) identified the RP2
gene. Using the YAC representation hybridization (YRH) technique, they
detected a LINE 1 (L1) insertion in 1 X-linked recessive retinitis
pigmentosa patient. Exon trapping experiments revealed a novel gene
found to encode a 350-amino acid protein. The predicted gene product
showed homology with human cofactor C (602971), a protein involved in
the ultimate step of beta-tubulin (191130) folding. Northern blot
hybridization with the cDNA revealed a 4-kb transcript in all fetal and
adult tissues examined. RT-PCR showed expression in adult human retina
using nested primers flanking the translation start and stop codons,
respectively, which amplified a fragment of 1.2 kb.

GENE FUNCTION

Chapple et al. (2000) identified putative sites for N-terminal acyl
modification by myristoylation and palmitoylation in the RP2 protein,
consistent with its primary localization in the plasma membrane in
cultured cells. Analysis of mutations in residues potentially required
for N-terminal acylation revealed that the palmitoyl moiety is
responsible for targeting of the myristoylated protein from
intracellular membranes to the plasma membrane.

By searching protein sequence databases, Schwahn et al. (2001)
determined that RP2 and cofactor C represent members of 2 distinct
orthologous groups. All previously identified missense mutations in RP2
affected amino acid residues which are conserved in all RP2 orthologs or
both orthologous groups. Studies of RP2-green fluorescent protein fusion
proteins in transiently transfected cells showed that a mutation in the
N terminus of RP2 abolished localization to the plasma membrane, whereas
C-terminal protein truncation mutations led to scattered fluorescent
foci in the cytoplasm. Western blot analysis failed to detect RP2
protein in immortalized cell lines from patients with protein truncation
mutations, while mRNA was still present. The authors concluded that loss
of RP2 protein and/or aberrant intracellular distribution might be the
basis for the photoreceptor cell degeneration in most RP2 cases.

The RP2 protein, like cofactor C, stimulates the GTPase activity of
tubulin in combination with cofactor D. RP2 has also been shown to
interact with ADP-ribosylation factor-like-3 (ARL3; 604695) in a
nucleotide- and myristoylation-dependent manner. Grayson et al. (2002)
examined the relationship between RP2, cofactor C, and ARL3 in
patient-derived cell lines and in the retina. Examination of
lymphoblastoid cells from patients with the arg120-to-ter mutation in
RP2 (R120X; 312600.0008) revealed that the expression levels of cofactor
C and ARL3 were not affected by the absence of RP2. In human retina, RP2
was localized to the plasma membrane in both rod and cone
photoreceptors, extending from the outer segment through the inner
segment to the synaptic terminals. In contrast, cofactor C and ARL3
localized predominantly to the photoreceptor-connecting cilium in rod
and cone photoreceptors. Cofactor C was cytoplasmic in distribution,
whereas ARL3 localized to other microtubule structures within all cells.
Grayson et al. (2002) suggested that RP2 may function in concert with
ARL3 to link the cell membrane with the cytoskeleton in photoreceptors
as part of the cell signaling or vesicular transport machinery.

Evans et al. (2010) showed in vitro that the RP2 gene product localized
to the ciliary apparatus, namely the basal body and the associated
centriole at the base of the photoreceptor cilium. Targeting to the
ciliary base was dependent on N-terminal myristoylation. RP2 also
localized to the Golgi and periciliary ridge of photoreceptors,
suggesting a role in regulating vesicle traffic and docking. KIF3A
(604683), a component of intraflagellar transport (IFT), is important in
cilia maintenance and transport of proteins through the connecting
cilium in photoreceptors. Similar to KIF3A and ARL3 (604695) depletion,
loss of RP2 led to fragmentation of the Golgi network. Depletion of RP2
and dysregulation of ARL3 resulted in dispersal of vesicles cycling
cargo from the Golgi complex to the cilium, including the IFT protein
IFT20 (614394). Evans et al. (2010) proposed that RP2 regulation of ARL3
is important for maintaining Golgi cohesion facilitating the transport
and docking of vesicles, and thereby carrying proteins to the base of
the photoreceptor connecting cilium for transport to the outer segment.

GENE STRUCTURE

Schwahn et al. (1998) determined that the RP2 gene contains 5 exons.

BIOCHEMICAL FEATURES

Veltel et al. (2008) solved the crystal structure of the central G
domain of mouse Arl3 bound to a GTP analog and human RP2 to 2.6-angstrom
resolution. Both switch regions of Arl3 interacted with the N-terminal
beta-helix domain of RP2. Biochemical analysis showed that Arl3 had a
slow intrinsic rate of GTP hydrolysis, which was accelerated more than
1,400-fold by catalytic amounts of RP2. Veltel et al. (2008) also
determined that arg118 of RP2 and gln71 of Arl3 were crucial active site
catalytic residues. They concluded that RP2 is a GTPase-activating
protein (GAP) for ARL3.

MOLECULAR GENETICS

In 6 patients with X-linked retinitis pigmentosa (RP2; 312600), Schwahn
et al. (1998) identified nonsense, missense, and frameshift mutations,
as well as 2 small deletions, in the RP2 gene.

*FIELD* AV
.0001
RETINITIS PIGMENTOSA 2
RP2, SER6DEL

In a patient with X-linked retinitis pigmentosa (RP2; 312600), Schwahn
et al. (1998) demonstrated a deletion of codon 6, TCC (serine), in the
RP2 gene. Chapple et al. (2000) showed that the ser6del mutation
interfered with the targeting of the protein to the plasma membrane.

.0002
RETINITIS PIGMENTOSA 2
RP2, GLN26TER

In a patient with X-linked retinitis pigmentosa (RP2; 312600), Schwahn
et al. (1998) demonstrated a change of codon 26 of the RP2 gene from CAG
(glutamine) to TAG (stop) (Q26X).

.0003
RETINITIS PIGMENTOSA 2
RP2, ARG118HIS

In a patient with X-linked retinitis pigmentosa (RP2; 312600), Schwahn
et al. (1998) demonstrated a change in codon 118 in exon 2 of the RP2
gene from CGT (arginine) to CAT (histidine) (R118H). The patient of
Schwahn et al. (1998) was from central Europe; Sharon et al. (2000)
reported the same mutation in a North American patient.

.0004
RETINITIS PIGMENTOSA 2
RP2, TYR151TER

In a patient with X-linked retinitis pigmentosa (RP2; 312600), Schwahn
et al. (1998) demonstrated a change in codon 151 in exon 2 of the RP2
gene from TAC (tyrosine) to TAG (stop) (Y151X).

.0005
RETINITIS PIGMENTOSA 2
RP2, 1-BP DEL

In a patient with X-linked retinitis pigmentosa (RP2; 312600), Schwahn
et al. (1998) demonstrated deletion of a cytosine (C) from codon 151
(TAC) of the RP2 gene, resulting in frameshift and 199 missing amino
acids from the gene product. The nucleotide deleted in this case was the
same as that which was mutated in the Y151X mutation (312600.0004).

.0006
RETINITIS PIGMENTOSA 2
RP2, ARG118LEU

Miano et al. (2001) identified a 354G-T transversion in exon 2 of the
RP2 gene, resulting in an arg118-to-leu amino acid change (R118L), as
the basis of an Italian case of X-linked retinitis pigmentosa (RP2;
312600). A mutation at the same codon, R118H (312600.0003), had
previously been reported, once from Central Europe (Schwahn et al.,
1998) and once from North America (Sharon et al., 2000).

.0007
RETINITIS PIGMENTOSA 2
RP2, 1-BP INS, 303T

In a Spanish case of X-linked retinitis pigmentosa (RP2; 312600), Miano
et al. (2001) found insertion of a T after nucleotide 303 in exon 2 of
the RP2 gene. The insertion caused a frameshift and a stop codon at
residue 123.

.0008
RETINITIS PIGMENTOSA 2
RP2, ARG120TER

In affected members of 3 apparently unrelated families with X-linked
retinitis pigmentosa (RP2; 312600), Hardcastle et al. (1999) identified
a C-to-T transition at nucleotide 358 in exon 2 of the RP2 gene,
resulting in a change of codon 120 from CGA (arg) to TGA (stop) (R120X).
The mutation resulted in truncation of the protein by 231 amino acids.
Vorster et al. (2004) identified the R120X mutation in 2 affected half
brothers; in the mother, an obligate carrier, no mutation could be
detected in somatic cells, suggesting germline mosaicism. They
speculated about the possibility of high mutability of a specific
nucleotide.

*FIELD* RF
1. Chapple, J. P.; Hardcastle, A. J.; Grayson, C.; Spackman, L. A.;
Willison, K. R.; Cheetham, M. E.: 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. Molec. Genet. 9:
1919-1926, 2000.

2. Evans, R. J.; Schwarz, N.; Nagel-Wolfrum, K.; Wolfrum, U.; Hardcastle,
A. J.; Cheetham, M. E.: The retinitis pigmentosa protein RP2 links
pericentriolar vesicle transport between the Golgi and the primary
cilium. Hum. Molec. Genet. 19: 1358-1367, 2010.

3. Grayson, C.; Bartolini, F.; Chapple, J. P.; Willison, K. R.; Bhamidipati,
A.; Lewis, S. A.; Luthert, P. J.; Hardcastle, A. J.; Cowan, N. J.;
Cheetham, M. E.: Localization in the human retina of the X-linked
retinitis pigmentosa protein RP2, its homologue cofactor C and the
RP2 interacting protein Arl3. Hum. Molec. Genet. 11: 3065-3074,
2002.

4. Hardcastle, A. J.; Thiselton, D. L.; Van Maldergem, L.; Saha, B.
K.; Jay, M.; Plant, C.; Taylor, R.; Bird, A. C.; Bhattacharya, S.
: Mutations in the RP2 gene cause disease in 10% of families with
X-linked retinitis pigmentosa assessed in this study. (Letter) Am.
J. Hum. Genet. 64: 1210-1215, 1999.

5. Miano, M. G.; Testa, F.; Filippini, F.; Trujillo, M.; Conte, I.;
Lanzara, C.; Millan, J. M.; De Bernardo, C.; Grammatico, B.; Mangino,
M.; Torrente, I.; Carrozzo, R.; Simonelli, F.; Rinaldi, E.; Ventruto,
V.; D'Urso, M.; Ayuso, C.; Ciccodicola, A.: Identification of novel
RP2 mutations in a subset of X-linked retinitis pigmentosa families
and prediction of new domains. Hum. Mutat. 18: 109-119, 2001.

6. Schwahn, U.; Lenzner, S.; Dong, J.; Feil, S.; Hinzmann, B.; van
Duijnhoven, G.; Kirschner, R.; Hemberger, M.; Bergen, A. A. B.; Rosenberg,
T.; Pinckers, A. J. L. G.; Fundele, R.; Rosenthal, A.; Cremers, F.
P. M.; Ropers, H.-H.; Berger, W.: Positional cloning of the gene
for X-linked retinitis pigmentosa 2. Nature Genet. 19: 327-332,
1998.

7. Schwahn, U.; Paland, N.; Techritz, S.; Lenzner, S.; Berger, W.
: Mutations in the X-linked RP2 gene cause intracellular misrouting
and loss of the protein. Hum. Molec. Genet. 10: 1177-1183, 2001.

8. Sharon, D.; Bruns, G. A. P.; McGee, T. L.; Sandberg, M. A.; Berson,
E. L.; Dryja, T. P.: X-linked retinitis pigmentosa: mutation spectrum
of the RPGR and RP2 genes and correlation with visual function. Invest.
Ophthal. Vis. Sci. 41: 2712-2721, 2000.

9. Veltel, S.; Gasper, R.; Eisenacher, E.; Wittinghofer, A.: The
retinitis pigmentosa 2 gene product is a GTPase-activating protein
for Arf-like 3. Nature Struct. Molec. Biol. 15: 373-380, 2008.

10. Vorster, A. A.; Rebello, M. T.; Coutts, N.; Ehrenreich, L.; Gama,
A. D.; Roberts, L. J.; Goliath, R.; Ramesar, R.; Greenberg, L. J.
: Arg120stop nonsense mutation in the RP2 gene: mutational hotspot
and germ line mosaicism? Clin. Genet. 65: 7-10, 2004.

*FIELD* CN
George E. Tiller - updated: 11/14/2011
Patricia A. Hartz - updated: 6/30/2009

*FIELD* CD
Anne M. Stumpf: 2/12/2009

*FIELD* ED
mgross: 12/13/2011
carol: 11/18/2011
terry: 11/14/2011
alopez: 7/6/2009
terry: 6/30/2009
alopez: 6/22/2009
alopez: 2/16/2009
alopez: 2/12/2009

MIM 312600
*RECORD*
*FIELD* NO
312600
*FIELD* TI
#312600 RETINITIS PIGMENTOSA 2; RP2
*FIELD* TX
A number sign (#) is used with this entry because this form of X-linked
read moreretinitis pigmentosa is caused by mutation in the RP2 gene (300757).

DESCRIPTION

Retinitis pigmentosa is characterized by constriction of the visual
fields, night blindness, and fundus changes, including 'bone corpuscle'
lumps of pigment. RP unassociated with other abnormalities is inherited
most frequently (84%) as an autosomal recessive, next as an autosomal
dominant (10%), and least frequently (6%) as an X-linked recessive in
the white U.S. population (Boughman et al., 1980).

For a phenotypic description and a discussion of genetic heterogeneity
of retinitis pigmentosa, see 268000.

CLINICAL FEATURES

The X-linked form of retinitis pigmentosa is also called choroidoretinal
degeneration, or pigmentary retinopathy. The gyrate choroidal atrophy
described by Waardenburg (1932) as X-linked was found on further study
to be retinitis pigmentosa (Waardenburg et al., 1961). As pointed out in
a review by Jacobson and Stephens (1962), there are some phenotypic
differences between reported families. The genetic significance of these
differences is unknown. There may be a fully recessive and an
intermediate X-linked form. Affected males show typical 'bone corpuscle'
clumps of pigment on funduscopic examination and progressive choroidal
sclerosis leading to complete blindness.

Hoare (1965) described a choroidoretinal disorder in 10 males in 7
sibships who were offspring of sisters. The maternal grandfather of the
affected males was probably also affected. The condition was detected in
childhood. Some carrier women showed fundus abnormalities with visual
impairment beginning in middle age and probably showing progression. The
condition in males resembled retinitis pigmentosa in fundus picture and
night blindness, but differed by the absence of annular scotoma, by
early involvement of central vision, and by relatively little vascular
change. In fact, many males with RP2 show choroidoretinal atrophy in the
advanced stages (Bird, 1975).

In 21 females heterozygous for X-linked RP (XLRP), Ernst et al. (1981)
found reduced flicker sensitivity over the whole frequency range where
thresholds could be tested.

Bundey and Crews (1986) concluded that the likelihood of an isolated
male with severe retinitis pigmentosa having the X-linked form is about
1 in 2; of 74 male index patients, 21 had X-linked disease. In the
family reported by Heck (1963), some heterozygous females were fully
affected and some showed only a blue-yellow color defect (a rare
anomaly). 'Tapetal reflex' was not present. The type of retinal
degeneration was variable, being pigmentary, nonpigmentary, or macular
in different affected males. Cataract was present in 2 with pigmentary
degeneration.

Fishman et al. (1988) profiled the clinical findings in 56 patients with
X-linked retinitis pigmentosa from 35 families.

Ultrastructural observations suggested that the rod photoreceptors are
severely affected by the mutation in this disorder. Because
photoreceptors develop from ciliated progenitors, it has been suggested
that the axoneme may play a role in the development of photoreceptors.
For this reason, Hunter et al. (1988) studied sperm axoneme structure in
8 patients with X-linked retinitis pigmentosa. A significant increase in
the percentage of abnormal sperm tails was observed. Similar
observations have been reported in Usher syndrome (276900).

Kaplan et al. (1990) suggested that phenotypically there are 2 forms of
X-linked RP: one form has very early onset with severe myopia (mean age
of onset = 3.5 years; 1 SD = 0.05); the other form starts later with
night blindness with or without mild myopia (mean age of onset = 10.6
years; 1 SD = 4.1). Kaplan et al. (1992) presented linkage evidence that
the clinical form with early myopia as the initial symptom is associated
with the RP2 gene, while the clinical form with later night blindness as
the initial symptom is associated with the RP3 gene.

Friedrich et al. (1993) found on reexamination of 7 obligate carrier
females and 6 daughters of obligate carriers whose linkage relationships
suggested that they carried the RP2 gene that the phenotype varied from
totally normal eyes through mild retinal changes to complete loss of
vision.

Grover et al. (2000) evaluated the progression of visual impairment in
carriers of X-linked recessive retinitis pigmentosa. They described the
relationship between retinal findings at presentation and the extent of
subsequent deterioration. They followed visual acuity, visual field, and
electroretinograms in 27 carriers of XLRP and described 4 grades of
fundus findings from grade 0 (normal) to grade 3 (diffuse changes). They
found that carriers of XLRP with only a tapetal-like retinal reflex
(grade 1) at presentation were more likely to retain visual function
than those with peripheral retinal pigmentation. Grover et al. (2000)
concluded that these data are useful in counseling such carriers as to
their visual prognosis.

Grover et al. (2002) compared the extent of intraocular light scatter
(straylight) in carriers of choroideremia (CHM; 303100) and the various
forms of XLRP to clarify the relationship between photoreceptor cell
degeneration and intraocular light scatter in hereditary retinal
degenerations. The carriers of XLRP who had evidence of photoreceptor
cell dysfunction (as determined by visual field loss and reduced
electroretinogram amplitudes) had increased levels of intraocular
straylight, whereas the carriers of CHM, who showed fundus abnormalities
alone, in the absence of demonstrable photoreceptor cell dysfunction,
had normal or minimally elevated levels of light scatter. The authors
concluded that the clinical symptom of glare, often reported by patients
with RP, results, at least in part, from increased intraocular
straylight caused by alterations in the optical quality of the
crystalline lens as a consequence of photoreceptor cell degeneration.

MAPPING

That the entity in the family reported by Hoare (1965) was identical to
(or allelic with) that discussed in this entry was established by
demonstration of identical linkage relationships (Bhattacharya et al.,
1985; Jay, 1987). In linkage studies with the L1.28 probe (DXS7),
Bhattacharya et al. (1984) found a maximum lod score of 7.89 at a
distance of 3 cM (95% confidence limits 0-15).

Friedrich et al. (1985) also published data on linkage with L1.28 (DXS7)
and C-banding heteromorphism. They concluded that the RP2 locus is close
to the centromere. RP2 lies between the centromere and DXS7. The same
group used centromeric heteromorphism to place Menkes disease (309400)
close to the centromere.

Clayton et al. (1986) summarized the data to that time on linkage to
DXS7. A maximum lod score of 14.01 at a theta of 0.08 was obtained.
There was no evidence for heterogeneity of recombination fraction among
the 13 families for which data were available. Wright et al. (1987)
analyzed linkage against Xp markers. The portion of the chromosome
distal to OTC was excluded as the location of RP2. The linkage observed
with OTC was theta = 0.19 (lod = 3.61). The most closely linked DNA
marker was DXS7 (theta = 0.09; lod = 8.66). Chen et al. (1987) found a
more distal location of the RP locus in 3 large pedigrees which may have
represented a separate disorder; heterozygotes showed the characteristic
tapetal reflex. In this family, OTC and RP2 seemed to be tightly linked
(lod = 10.64; theta = 0.00). It was presumably RP3 (300029) that Chen et
al. (1987) were dealing with in this family. Litt et al. (1987) found no
recombination of RP2 with DXS7 or with DXZ1, a centromeric site detected
by an alpha-satellite probe. On the basis of a study of 20 kindreds,
Wright et al. (1987) concluded that X-linked RP lies proximal to DXS7,
which has been mapped to Xp11.3. Meitinger et al. (1989) demonstrated
linkage to an informative hypervariable marker defining the DXS255
segment; theta = 0.07 at a maximum lod of 4.75. Farrar et al. (1988)
contributed linkage data to the question of heterogeneity in X-linked
RP. Chen et al. (1989) presented further data supporting the existence
of 2 separate RP loci on Xp; by multipoint linkage analysis with 10 loci
in 9 affected families, the mutation mapped telomeric to DXS7 in 7 and
centromeric to DXS7 in 2. Microsatellites are stretches of tandemly
repeated dinucleotides, such as poly(dGdT).(dCdA), which are widely
distributed throughout eukaryotic genomes. Many microsatellites are
hypervariable by reason of a variable number of dinucleotide repeats.
Such polymorphisms can be studied by using PCR to amplify across the
repeats and then resolving size differences (multiples of dinucleotides)
in the PCR product by PAGE (Litt and Luty, 1989; Weber and May, 1989).
Coleman et al. (1990) found that one such polymorphic microsatellite,
DXS426, maps to Xp11.4-p11.22. They used this information for refinement
of the location of the RP2 gene, which they concluded lies between
DXS426 and DXS7. Wright et al. (1991) found no recombination with DXS255
(in Xp11.22) or TIMP (in Xp11.3-p11.23; 305370).

Friedrich et al. (1992) used DNA markers and the cytogenetic centromere
marker for linkage mapping in a large Danish family. They found the
highest location score for a site distal to DXS255 and proximal to the
OTC locus. In comparison with the first large Danish family that
Friedrich et al. (1985) had studied, the recombination fraction between
the centromere and the proximal genetic marker on the short arm, DXS7,
was 0.17, which corresponded to the distance 18 cM recorded by HGM10
(Keats et al., 1989). However, in the second Danish family (Friedrich et
al., 1992), the pericentric recombination fraction was increased,
leading them to speculate that the difference in the size and location
of the centromeric heterochromatin was responsible. Involvement of
centromeric heterochromatin in recombination is well known in
Drosophila; recombination in the euchromatin near the centromere is
usually reduced, the so-called centromere effect. Variability in the
position and amount of heterochromatin was observed between the 2
families. Another finding of note in the second family was the presence
of several blind female carriers and a few female carriers with no
phenotypic signs on thorough ophthalmologic examination and full field
electroretinography (Friedrich et al., 1992).

Thiselton et al. (1996) reported a defined localization for the RP2 gene
to a 5-cM interval in Xp11.3-p11.23.

MOLECULAR GENETICS

In 6 patients with X-linked retinitis pigmentosa, Schwahn et al. (1998)
detected 6 different mutations in a novel gene (RP2; 300757).

In a cohort of North American families with X-linked retinitis
pigmentosa, Mears et al. (1999) reported 5 protein truncation mutations
of the RP2 gene. These were different from the 7 reported in European
families by Schwahn et al. (1998), suggesting a high rate of new
mutations and a lack of founder effect.

Chapple et al. (2000) identified putative sites for N-terminal acyl
modification by myristoylation and palmitoylation in the RP2 protein,
consistent with its primary localization in the plasma membrane in
cultured cells. Mutations in residues potentially required for
N-terminal acylation revealed that the palmitoyl moiety is responsible
for targeting of the myristoylated protein from intracellular membranes
to the plasma membrane. The ser6del mutation (300757.0001) interfered
with targeting of the protein to the plasma membrane, suggesting to the
authors that the ser6del mutation may cause XLRP because it prevents
normal amounts of RP2 from reaching the correct cellular locale. The
R118H mutation (300757.0003) did not have a similar effect on
localization.

Miano et al. (2001) identified 5 novel mutations in RP2, each in a
different XLRP family. These mutations included 3 missense mutations, a
splice site mutation, and a single base insertion, which, because of a
frameshift, led to a premature stop codon.

Grayson et al. (2002) examined the relationship between RP2, cofactor C
(602971), and ARL3 (604695) in patient-derived cell lines and in the
retina. Examination of lymphoblastoid cells from patients with the
arg120-to-ter mutation in RP2 (R120X; 300757.0008) revealed that the
expression levels of cofactor C and ARL3 were not affected by the
absence of RP2.

BIOCHEMICAL FEATURES

Using the highly informative probe M27-beta that detects the DXS255
locus, which is differentially methylated on the active and inactive X
chromosomes, Friedrich et al. (1993) determined the methylation status
of the RP2 gene in 7 obligate carrier females and 6 daughters of
obligate carriers, all from the same family, whose linkage relationships
suggested that they carried the RP2 gene. In 5 blind heterozygotes (aged
43 to 68 years), they found that the X chromosome carrying the RP2 gene
was methylated and active in nearly all cells. The opposite
X-inactivation pattern was found in a carrier female, aged 45 years, who
gave normal findings on eye examination. Carriers with less skewed X
inactivation had a less severe clinical outcome. However, Friedrich et
al. (1993) found little or no correlation between phenotypes and the
methylation status of the X chromosomes.

PATHOGENESIS

By searching protein sequence databases, Schwahn et al. (2001)
determined that RP2 and cofactor C represent members of 2 distinct
orthologous groups. All previously identified missense mutations in RP2
affected amino acid residues which are conserved in all RP2 orthologs or
both orthologous groups. Studies of RP2-green fluorescent protein fusion
proteins in transiently transfected cells showed that a mutation in the
N terminus of RP2 abolished localization to the plasma membrane, whereas
C-terminal protein truncation mutations led to scattered fluorescent
foci in the cytoplasm. Western blot analysis failed to detect RP2
protein in immortalized cell lines from patients with protein truncation
mutations, while mRNA was still present. The authors concluded that loss
of RP2 protein and/or aberrant intracellular distribution might be the
basis for the photoreceptor cell degeneration in most RP2 cases.

HETEROGENEITY

Teague et al. (1994) analyzed 40 kindreds with X-linked retinitis
pigmentosa for linkage heterogeneity, concluding that 56% were of the
RP3 type and 26% of the RP2 type. Bayesian probabilities of linkage to
RP2, RP3, or to neither locus were calculated. This showed that 20 of 40
kindreds could be assigned to one or the other locus, with a probability
of more than 0.70 (14 RP3 kindreds and 6 RP2 kindreds). A further 3
kindreds were found to be unlinked to either locus, with a probability
of more than 0.8. The remaining 17 kindreds could not be classified
unambiguously. This highlighted the difficulty of classifying families
in the presence of genetic heterogeneity, where the 2 loci are separated
by an estimated 16 cM.

Aldred et al. (1994) described RP2 and RP3 regions of Xp. In one case,
reassessment of the family in light of these results suggested that the
affected individuals may, in fact, have an autosomal dominant form of
RP. The remaining 2 families were consistent with X linkage and
suggested the possibility of a new X-linked RP locus.

Miano et al. (2001) stated that as many as 5 distinct loci on the X
chromosome determine X-linked retinitis pigmentosa, but only 2 XLRP
genes had been identified: RPGR (312610) and RP2. Mutations in these
genes account for approximately 70% and 10% of XLRP patients,
respectively. Clinically, there are no clearly significant differences
between RP3 and RP2 phenotypes.

Sharon et al. (2003) screened 187 unrelated male patients for mutations
in the RP2 and RPGR genes, including 135 with a prior clinical diagnosis
of XLRP, 11 with probable XLRP, 30 isolated cases suspected of having
XLRP, and 11 with cone-rod degeneration. Among the 187 patients, they
found 10 mutations in RP2, 2 of which were novel, and 80 mutations in
RPGR, 41 of which were novel; 66% of the RPGR mutations were within
ORF15. Among the 135 with a prior clinical diagnosis of XLRP, mutations
in the RP2 and RPGR genes were found in 9 of 135 (6.7%) and 98 of 135
(72.6%), respectively, for a total of 79% of patients. Patients with RP2
mutations had, on average, lower visual acuity but similar visual field
area, final dark-adapted threshold, and 30-Hz ERG amplitude compared
with those with RPGR mutations.

Pelletier et al. (2007) reported the screening of the RP2 and RPGR genes
in a cohort of 127 French families comprising 93 familial cases of
retinitis pigmentosa suggesting X-linked inheritance, including 48 of 93
families; 7 male sibships of RP; 25 sporadic male cases of RP; and 2
cone dystrophies (COD). They identified a total of 14 RP2 mutations, 12
of which were novel, in 14 of 88 familial cases of RP and 1 of 25
sporadic male cases (4%). In 13 of 14 of the familial cases, no
expression of the disease was noted in females, while in 1 of 14
families 1 woman developed retinitis pigmentosa in the third decade. A
total of 42 RPGR mutations, 26 of which were novel, were identified in
80 families, including 69 of 88 familial cases (78.4%); 2 of 7 male
sibship cases (28.6%); 8 of 25 sporadic male cases (32%); and 1 of 2
COD. No expression of the disease was noted in females in 41 of 69
familial cases (59.4%), while at least 1 severely affected woman was
recognized in 28 of 69 families (40.6%). The frequency of RP2 and RPGR
mutations in familial cases of retinitis pigmentosa suggestive of
X-linked transmission was in accordance with that reported elsewhere
(RP2: 15.9% vs 6-20%; RPGR: 78.4% vs 55-90%). About 30% of male sporadic
cases and 30% of male sibships of RP carried RP2 or RPGR mutations,
confirming the pertinence of the genetic screening of XLRP genes in male
patients affected with RP commencing in the first decade and leading to
profound visual impairment before the age of 30 years.

HISTORY

Spence et al. (1974) analyzed a large pedigree in which some
heterozygous females had full-blown RP, making it difficult to
distinguish X-linked from autosomal dominant inheritance with reduced
penetrance. A computerized analysis indicated that the X-linked model is
more than 1,000 times more likely than the autosomal model. Gieser et
al. (1980) suggested that vitreous fluorophotometry may be a sensitive
method for detecting heterozygous females. Grutzner et al. (1972)
concluded that the loci for RP, for Xg blood group, and for color vision
are widely separated on the X chromosome.

ANIMAL MODEL

Acland et al. (1994) described an X-linked retinal degeneration in the
Siberian Husky dog that they suggested might be a homolog of RP2 or one
of the other forms of X-linked retinitis pigmentosa.

*FIELD* SA
Allan (1937); Falls (1952); Klein et al. (1967); McQuarrie (1935);
Mukai et al. (1985); Usher (1935); Warburg and Simonsen (1968); Wright
et al. (1987)
*FIELD* RF
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720 only, 1987.

*FIELD* CS

Eyes:
Retinitis pigmentosa;
Choroidoretinal degeneration;
Pigmentary retinopathy;
Gyrate choroidal atrophy;
Constricted visual fields;
Night blindness;
Cataract;
Early myopia

Misc:
Some heterozygous females show a blue-yellow color defect

Inheritance:
X-linked recessive form (least frequent at 6%);
autosomal recessive (84%) or autosomal dominant (10%)

*FIELD* CN
Marla J. F. O'Neill - updated: 10/5/2010
Marla J. F. O'Neill - updated: 6/29/2010
Victor A. McKusick - updated: 3/28/2007
Victor A. McKusick - updated: 2/25/2004
Victor A. McKusick - updated: 12/12/2003
Jane Kelly - updated: 3/20/2003
George E. Tiller - updated: 10/17/2001
Victor A. McKusick - updated: 9/20/2001
George E. Tiller - updated: 10/20/2000
Jane Kelly - updated: 6/28/2000
Victor A. McKusick - updated: 4/13/1999
Victor A. McKusick - updated: 7/27/1998

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
alopez: 10/14/2010
wwang: 10/6/2010
terry: 10/5/2010
carol: 6/29/2010
carol: 3/3/2010
wwang: 7/21/2009
alopez: 7/14/2009
terry: 3/31/2009
alopez: 2/16/2009
alopez: 2/12/2009
carol: 6/10/2008
alopez: 4/3/2007
terry: 3/28/2007
carol: 3/10/2006
terry: 9/27/2005
carol: 9/29/2004
tkritzer: 8/25/2004
terry: 6/3/2004
tkritzer: 2/26/2004
terry: 2/25/2004
cwells: 12/16/2003
terry: 12/12/2003
cwells: 3/20/2003
carol: 3/20/2003
alopez: 4/18/2002
cwells: 10/30/2001
cwells: 10/17/2001
mcapotos: 10/2/2001
mcapotos: 9/24/2001
terry: 9/20/2001
carol: 11/1/2000
mcapotos: 10/20/2000
alopez: 6/28/2000
carol: 4/14/1999
terry: 4/13/1999
alopez: 7/31/1998
alopez: 7/30/1998
terry: 7/27/1998
dkim: 7/7/1998
jenny: 12/12/1996
terry: 12/10/1996
carol: 3/2/1995
terry: 8/30/1994
davew: 7/25/1994
warfield: 3/14/1994
mimadm: 2/28/1994
carol: 12/16/1993

RBCC Red Blood Cell Collection

Full text data of RP2