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Human Molecular Genetics Pages 1035-1041
Positional cloning of the gene for X-linked retinitis pigmentosa 3: homology with the guanine-nucleotide- exchange factor RCC1
Introduction
Results
   Identification of protein coding sequences from the RP3 critical region
   Detection of point mutations in patients with X-linked RP
Discussion
Materials And Methods
   Construction of a cosmid library
   Screening of cDNA libraries
   DNA sequencing and data processing
   mRNA isolation and RT-PCR
   Single strand conformation polymorphism (SSCP) analysis
Acknowledgements
References

Positional cloning of the gene for X-linked retinitis pigmentosa 3: homology with the guanine-nucleotide- exchange factor RCC1

Positional cloning of the gene for X-linked retinitis pigmentosa 3: homology with the guanine-nucleotide- exchange factor RCC1 Ronald Roepman1, Gerard van Duijnhoven1, Thomas Rosenberg2, Alfred J. L. G. Pinckers3, Liesbeth M. Bleeker-Wagemakers4, Arthur A. B. Bergen4, Jan Post5, Alfred Beck6, Richard Reinhardt6, Hans-Hilger Ropers1,6, Frans P. M. Cremers1 and Wolfgang Berger6,*

Departments of 1Human Genetics and 3Ophthalmology, University Hospital Nijmegen, Nijmegen, The Netherlands, 2National Eye Clinic for the Visually Impaired, Hellerup, Denmark, 4Department of Ophthalmogenetics, Ophthalmic Research Institute, Amsterdam, The Netherlands, 5Clinical Genetics Center, Utrecht, The Netherlands and 6Max-Planck-Institut für Molekulare Genetik, Berlin, Germany

Received April 29, 1996; Accepted May 2, 1996EMBL accession no. X97668

The gene for retinitis pigmentosa 3 (RP3), the most frequent form of X-linked RP (XLRP), has been mapped previously to a chromosome interval of less than 1000 kbp between the DXS1110 marker and the OTC locus at Xp21.1-p11.4. Employing a novel technique, `YAC Representation Hybridization (YRH)', we have recently identified a small XLRP associated microdeletion in this interval, as well as several putative exons including the 3' end of a gene that was truncated by the deletion. cDNA library screening and sequencing of a cosmid centromeric to the deletion has now enabled us to identify numerous additional exons and to detect several point mutations in patients with XLRP. The predicted gene product shows homology to RCC1, the guanine-nucleotide-exchange factor (GEF) of the Ras-like GTPase Ran. Our findings suggest that we have cloned the long-sought RP3 gene, and that it may encode the GEF of a retina-specific GTP-binding protein.

INTRODUCTION

Retinitis pigmentosa (RP), a heterogeneous group of disorders characterized by night blindness, progressive constriction of the visual field and `pigmented' fundus abnormalities, is due to the gradual degeneration of photoreceptor cells which begins in the periphery and progresses to the central region of the retina. In advanced stages, patients present with tunnel vision and may become legally blind. About 80% of the patients have autosomal recessive forms of RP. Autosomal dominant and the more severe X-linked RP (XLRP) account each for approximately 10% of the cases, but in Denmark and the UK, a much higher proportion of XLRP has been reported (1 ,2 ).

At least three different gene loci are involved in X-linked retinitis pigmentosa (XLRP), which have been mapped by linkage studies and heterogeneity testing to Xp11.2-p11.4 (RP2), Xp11.4-p21.1 (RP3) and farther distal on Xp (RP6), respectively (3 -5 ). By molecular characterization of two deletions in patients with RP and other X-linked disorders, the gene for the most frequent form of XLRP, retinitis pigmentosa 3 (RP3), has been assigned previously to an interval of less than 1000 kilobases (kb) between the DXS1110 marker and the ornithine transcarbamylase (OTC) gene (6 ).

In previous studies by our group that led to the molecular elucidation of two other eye disorders (7 ,8 ), intragenic microdeletions of a few kbp had been instrumental for fine mapping and cloning of the respective genes. With conventional (Southern blotting and PCR based probe screening) techniques, such small microdeletions are difficult to find, however, even in genomic intervals of 1000 kb or less. To overcome this difficulty, we have recently developed a novel `YAC Representation Hybridisation' technique which was employed for microdeletion screening in the chromosomal interval carrying the RP3 gene (9 ). In one out of 30 patients with XLRP, a 6.4 kb microdeletion was detected. By sequencing of a cosmid spanning this deletion and by cDNA library screening, several exons were found, including the 3' end of a gene that was partially deleted in this patient. None of these exons contained an open reading frame, however, and the search for point mutations in patients with XLRP was unsuccessful.

Therefore, in order to identify additional exons from the 5' end of this gene, we have now isolated and sequenced a neighboring cosmid from a previously established cosmid contig, as well as two EcoRI fragments separating this cosmid from the (more distal) one that had been sequenced previously. Computer-assisted analysis of this sequence predicted numerous additional exons which could be confirmed by cDNA cloning and sequencing, and in several patients with XLRP, small mutations were detected which were not observed in healthy controls. Sequence comparisons have revealed that the deduced product of this gene shows strong structural similarities with RCC1, the guanine nucleotide exchange factor of the Ras-like GTPase Ran. These findings suggest that we have identified the long-sought RP3 gene, and they may provide a clue to its role in the pathogenesis of retinitis pigmentosa.

RESULTS

Identification of protein coding sequences from the RP3 critical region

In order to extend the cDNA of a previously identified candidate gene for RP3 (9 ) in the 5' direction, we have sequenced the neighboring cosmid clone ICRFB0972 (see Fig. 1 ) by a shotgun approach. Sequence data were assembled in 15 contigs, covering 39.776 bp proximal to the cosmid LL242D12 (Fig. 1 ), which was sequenced recently (9 ). Moreover, the gap between these two cosmids was closed by sequencing two intervening 8.0 and 5.8 kbp EcoRI fragments by primer walking. In total, we have sequenced approximately 75 kbp from the genomic region carrying the RP3 gene. In parallel another cosmid, cT-A5, was employed to screen a cDNA library from adult retina. This cosmid clone which is almost identical to cosmid ICRFB0972 was derived from a cosmid library of YAC ICRFy900E0701 (see Fig. 1 ). The cDNA screening revealed six positive clones, four of which were characterized in more detail by Southern blot hybridization and sequence analysis. Seven partially overlapping cDNA clones were assembled by using the program GELMERGE (10 ). The resulting cDNA consensus sequence was aligned to genomic sequences from cosmids ICRFB0972 and LL242D12 and the 8.0 and 5.8 kbp EcoRI fragments. In this way 12 additional exons were identified (Figs 1 and 2 ). One hundred and one nucleotides at the 3' end of the consensus cDNA sequence did not match genomic sequences which points to a gap in our genomic sequence contig. Since the penultimate exon of the cDNA is present on the 5.8 kbp EcoRI fragment, this gap is most likely between this and the adjacent 8.0 kbp EcoRI fragment. Five of the exons were also identified by the GRAIL exon prediction program (releases 2.0 and 1.3, see Materials and Methods).


Figure 1. Physical map of the region containing the RP3 gene. The upper part of the figure shows the cosmid contig covering the region between the 3' end of the RP3 gene and the 5' end of the OTC gene. Cosmids derived from the ICRF and Lawrence Livermore (LL) libraries were published previously (9). Clones cT-A5 and -D4 were isolated from a library generated by subcloning a YAC (see Materials and Methods). The lower part of this figure displays the EcoRI restriction map and exon distribution in a 70 kbp region harboring the RP3 gene. Cosmid clones LL242D12 and ICRFB0972 were sequenced. The sequence contig was completed by sequencing the 8.0 and 5.8 kbp fragments between them. Exons were identified by aligning cDNA and genomic sequences. Fragments U-V were described previously (9), and all other exon fragments correspond to cDNAs which were isolated by screening a retina library with cosmid clone cT-A5. Primer numbers given for 10 of the novel exons refer to Table 1. The asterisks indicate fragments containing sequence alterations confined to patients.


Figure 2. cDNA consensus sequence with the deduced protein translation. The boundaries between the different exons are represented by arrowheads. The sequence contains a reading frame, encoding 518 amino acid residues. A translation start site was not identified, indicating an incomplete 5' end.

Northern blot hybridization with a probe containing 1177 bp from the 5' end of the cDNA detected a transcript of approximately 3 kbp in heart, brain, placenta, lung, liver, skeletal muscle, and pancreas (Fig. 3 ). A FASTA search with the consensus cDNA sequence of 1557 bp failed to detect significant homologies with GENEMBL entries. It contains a contiguous reading frame of 518 amino acid residues (Fig. 2 ), which was used to perform database searches by employing the BLASTP as well as the FASTA programs (10 ). Significant homologies were detected with RCC1 proteins from several species, including human, hamster, Xenopus, Drosophila, and yeast. The most significant homology was observed with human, hamster and Xenopus RCC1 proteins, i.e. approximately 30% identity within an overlap of 450 amino acid residues. Amino acid identity with the Drosophila and yeast RCC1 peptides was 26 and 20%, respectively.


Figure 3. Autoradiograph of a Northern blot containing poly(A)+-RNA from various adult tissues after hybridization with a cDNA probe containing 1177 bp from the 5' end of the cDNA presented in Figure 2. Sizes of the marker fragments are given in kbp. The size of the detected transcript was estimated as 3 kbp approximately.

In a previous study (9 ), we had identified the 3' end of a gene, which was disrupted in one patient with XLRP by a 6.4 kbp microdeletion. The six exons (fragments U-Z, see Figure 1 ) showed no disease related sequence alterations but several polymorphisms. RT-PCR experiments have now revealed that these exons belong to the gene presented here. By using an antisense primer from exon W (Fig. 1 ) in combination with a sense primer from position 472-492 of the consensus cDNA (Fig. 2 ), a 1.5 kbp fragment was amplified, and sequence analysis from both ends of the PCR product confirmed the identity of the exons. In total, 2.7 kbp of cDNA sequence were identified, representing at least 18 exons of one gene.

Detection of point mutations in patients with X-linked RP

Mutation screening was carried out in 28 XLRP patients by means of SSCP analysis. Intron primers were designed for the PCR amplification of 10 exons (see Table 1 ). Five bandshifts were observed in patients but not in controls, indicating disease-specific sequence alterations. The corresponding PCR fragments were sequenced which revealed three different nucleotide exchanges and one 4 bp deletion in five patients (see Fig. 4 ). Patient 4767 carried a T to G transversion at nucleotide position 420, resulting in the substitution of phenylalanine by cysteine. A proline to serine exchange was shown to be the consequence of a C to T transition at position 734 of the cDNA sequence in patient 2884. Another serine residue was generated due to a G to A exchange at postion 854 in patients 2603 and 2555. Strikingly, the two mutations that give rise to a serine residue are located in a highly conserved domain of the protein which shows 40% identity in a 57 amino acid segment of the RCC1 consensus sequence (RCC1_2.PRF, derived from release 10.0 of PROSITE, see underlined residues in Fig. 4 ). Moreover, the amino acid substitution in patients 2555 and 2603 affect a glycine residue which is highly conserved during evolution (Fig. 4 , position 331). A 4 bp deletion was observed in patient 2550 (nucleotides 1433-1436), resulting in a truncated protein with six abnormal C-terminal amino acids, including a conserved glutamic acid residue (see Figs 4 and 5 ). None of these changes was detected in 84 male controls.

Table 1 . Oligonucleotide primers used for PCR amplification, SSCP screening, and sequencing of exon fragments from the RP3 gene
Primer ID

 Sequence (5' -> 3')

 Fragment size (bp)

 cDNA contained
210

 gta gtt ctc ata gta ttc tta cca

 235

 716-809
211

 tta ggt ctt ccc aat cag ctc

  
 

  
212

 ttc aga cac cag ctg ggg tg

 204

 651-725
213

 caa atg tat taa gtg atc ctt gtc

  
 

  
214

 caa ctt tta gga aag ttt ata tca at

 289

 1276-1456
215

 aag gca cat tta tcc tga gag c

  
 

  
218

 gtg tct gct tcc ata atc ctt g

 259

 810-963
219

 tgt aat aaa ata tac cca gtt cta ta

  
 

  
220

 ctg gaa tga gac ctc agt tct c

 190

 276-338
221

 cat ttg tcc tgg act act gtt ca

  
 

  
222

 gga ctc tat agt cta ttg acg tt

 238

 339-500
223

 agg gaa tgt gtc cca gac tga a

  
 

  
224

 gct tca gag cct ggc tac ct

 256

 501-650
225

 aca aca tag aag tgg gag ata ac

  
 

  
226

 ata gat cca tac aag taa cac ttt

 250

 964-1092
227

 tcc atg aaa tac tga aag act ca

  
 

  
228

 cag tgc tag ata ata cta tta tac

 273

 1093-1275
229

 tga agc caa tgt tga tga gtt t

  
 

  
217

 gtt att tta ata aca ggc aac ata g

 266

 59-180
230

 aca cag cag cat atc tat aac aa

  
 

  
231

 tga cat taa aga act aca cag tca

 229

 181-275
232

 tga cct cat ctt aca tta tgt gaa

  

  

In addition to these apparently disease-specific changes we have detected two polymorphisms. One was a G to A transition at position 1305 of the cDNA sequence, resulting in a substitution of arginine by leucine. This change was present in two patients with X-linked RP but also in two out of 86 controls and in the sequence of cosmid ICRFB0972. The second polymorphism was detected at position 1322 (A to G, isoleucine to serine), present in one patient and in five out of 86 controls. Both exchanges represent conservative amino acid substitutions and involve a domain of the predicted gene product that is not homologous to RCC1 proteins.

DISCUSSION


Figure 4. Sequence alignment of RCC1 proteins from different species by using the PILEUP program. Peptide sequences for the human, hamster, Xenopus, Drosophila and yeast RCC1 molecules are derived from the Swiss.prot database (accession numbers P18754, P23800, P25183, P25171, P21827). Amino acid residues conserved between the RCC1 polypeptides and the predicted RP3 gene product are depicted in bold. The RCC1-profile (RCC1_2.PRF, derived from release 10.0 of PROSITE) is underlined. Changes in the amino acid sequence, detected in patients only, are indicated by: mut 4767 (position 145), mut 2884 (position 270), mut 2555/2603 (position 331) and mut 2550 (positions 540-546)


Figure 5. Sequencing patterns from PCR products of controls (top) and patients (bottom). The PCR amplification was performed with primer pairs (a) 218 & 219 and (b) 214 & 215, and sequencing reactions were carried out with primers 218 and 214, respectively.

RP3, the gene for the most frequent form of XLRP, had long been known to map to an interval of less than 1000 kbp between the DXS1110 marker and the OTC gene at Xp11.4-p21.1 (3 -6 ,11 ) but numerous efforts to isolate this gene by positional cloning had remained unsuccessful. By making use of a novel `YAC Representation Hybridization' approach, to screen this interval for microdeletions, we have recently detected a 6.4 kbp deletion in a patient with XLRP (9 ). Molecular characterization and sequencing of cosmids and cDNAs spanning this deletion enabled us to define the last six exons of a gene that was expressed in various tissues including retina, and this cDNA was also contained in a larger deletion described by others (12 ). Here we describe the identification of six novel retina cDNAs and 12 corresponding exons which could be linked to the previously isolated cDNA by RT-PCR and represent the middle and 5' portion of the same gene. This gene encodes a protein of at least 518 amino acids; the outermost sequences of the ORF have not yet been identified. The predicted protein shows significant homology to the guanine nucleotide exchange factor RCC1 of several species. In five out of 28 patients with XLRP, small sequence alterations were found which were not observed in 84 control males and are therefore considered as disease-specific mutations. In two apparently unrelated patients, the same mutation was observed.

So far, mutations in the RP3 gene have only been detected in 18% of the patients with XLRP, which is at variance with linkage studies suggesting that RP3 accounts for at least two-thirds of the familial cases. There are several possible explanations for this discrepancy. First, systematic mutation screening has only been done so far in 16 out of 18 exons identified. Secondly, we have not yet found all exons of the RP3 gene; at the 5' end, at least one exon is still missing, and the promotor region of this gene, which has not yet been cloned, might also harbour several of the `missing' mutations. Mutations in the RP2 gene, located in the Xp11.2-p11.4 region proximal to RP3, is thought to be involved in almost one-third of the cases-but then, the contribution of RP2 and RP3 mutations in XLRP is not well defined and may vary in different populations. Finally, the possibility cannot be ruled out that there is yet another XLRP gene in the vicinity of RP3.

The predicted amino acid sequence of the RP3 gene identified in this study shows the highest homology (31.5%) with the human RCC1 protein (13 ), which acts as a guanine-nucleotide-exchange factor (GEF) of Ran, a GTPase which recently was shown to be involved in nuclear protein import (14 ). GEFs associate with GDP-bound forms of GTPases and accelerate GDP dissociation and GTP binding, thereby activating the GTPase. A large number of GEFs have been identified, most of which are involved in Ras signalling (15 ). RCC1 is composed of seven repeats of about 60 residues each. The RP3 gene thus far is the only gene showing homology to RCC1. In another X-linked eye disorder, choroideremia, the defective gene plays a role in the geranylgeranylation of several different Rab proteins, another family of Ras-related GTPases (7 ,16 ). In view of the clinical similarities between choroideremia and RP3, it is tempting to speculate that the RP3 protein might function as a GEF for retina specific Rab proteins. Thus far, two different rabGEFs, i.e. Mss4 (mammalian suppressor of sec4) and Dss4-1 (dominant suppressor of sec4) have been cloned (17 ,18 ). These proteins do not show any sequence similarity to RCC1 or other GEFs, nor to the RP3 protein described here. Given the large number of GEF molecules involved in ras signalling, the RP3 protein might represent the first member of a new family of GEFs regulating the activity of rabs or related GTPases.

Previously, the presymptomatic diagnosis and carrier detection in XLRP families has been severely hampered by the genetic heterogeneity of this disorder and particularly by the fact that neither clinically nor genetically, RP3 and RP2 could be reliably distinguished. Therefore, the direct detection of RP3 mutations in presymptomatic affected males and female carriers will also facilitate the diagnosis in other forms of XLRP, and the molecular elucidation of the fundamental defect underlying RP3 may be a clue to the etiology and pathogenesis of RP2, too.

MATERIALS AND METHODS

Construction of a cosmid library

In order to construct a complete cosmid contig from the RP3 critical region we have subcloned the YAC ICRFy900E0701 into the sCOGH2, an improved version of the recently described cosmid vector sCOGH1 (19 ). The cosmid library was prepared as described previously (8 ). Briefly, YAC DNA was partially digested with the restriction enzyme Sau3A, separated on a sucrose gradient, and the fraction between 30-40 kbp was cloned into the BamHI digested sCOGH2 vector. The ligation mix was packaged by using Stratagene packaging extract (Gold), and 4200 resulting colonies were screened with human placenta DNA. One hundred and forty-four clones containing human DNA inserts were picked and gridded on Nylon membrane (GeneScreenPlus). The contig between the previously identified RP3 candidate gene (9 ) and OTC was completed by hybridizing these grids with cosmids LL242D12 and ICRFB0972 as well as the OTC cDNA probe.

Screening of cDNA libraries

The NotI insert of cosmid cT-A5 was used to screen a cDNA library, established from adult retina (courtesy of J. Nathans). Screening of 2 million p.f.u. of each library, plated on E.coli LE392, was performed as described previously (8 ). Positive plaques were purified and phage DNA was prepared by using the Qiagen Lambda kit. Inserts were isolated preparatively and subcloned into the pGEM3 vector.

DNA sequencing and data processing

Shotgun cosmid sequencing was performed by dye-primer chemistry on an ABI377 automated sequencer as described previously (9 ). Assembly of the data was achieved by using the Staden package. Sequencing of the two genomic EcoRI fragments (8.0 and 5.8 kbp) and the cDNA clones was carried out by primer walking on subcloned fragments using the DyeDeoxy terminator cycle sequencing kit (ABI). The data were assembled by the GELMERGE program. Exon-intron boundaries were determined by aligning the cDNA sequences to the genomic sequence contig by using BESTFIT and FASTA programs. Prediction of putative exon sequences was done by GRAIL, using releases 2.0 and 1.3 from the GRAIL e-mail server (grail@ornl.gov).

mRNA isolation and RT-PCR

Total RNA was isolated from Hela cells as described elsewhere (20 ) and poly A+ mRNA was isolated using the oligotex mRNA kit (QIAgen). RT-PCR was performed mainly as described elsewhere (20 ), using the sense primer 57 (5'-TGGATCTAATACTTCAGCTGC) and the antisense primer 1136 (5'-GTTTCAGCTGAGCTATCATCA) for PCR amplification of the cDNA products. 35 cycles of denaturation at 95oC for 1 min, annealing at 58oC for 2 min and extension at 72oC for 3 min were carried out with an initial denaturation step of 5 min and a final extension step of 6 min. The PCR products were analysed on a 1.5% agarose gel, purified using the QIAquick gel extraction kit (QIAgen) and sequenced as described above.

Single strand conformation polymorphism (SSCP) analysis

Exon fragments from patients and controls were amplified with intron primers as described (9 ). The primer sequences, the corresponding positions within the cDNA and sizes of the fragments are summarized in Table 1 . SSCP-PCR was carried out in the presence of [alpha][32P]dCTP, and the denatured radiolabeled fragments were separated in a non denaturing polyacrylamide gel as described (21 ). Sequencing of aberrant PCR fragments was performed by dyedeoxy termination cycle sequencing (ABI) on an ABI370A automated sequencer.

ACKNOWLEDGEMENTS

The authors are grateful to the patients and their families for contributing to this study and making available their blood for DNA isolation. We would like to acknowledge the efforts of S. van der Velde-Visser and L. Boender-van Rossum for establishing immortalized cell lines from the patients and their carrier mothers, and Sven Klages and Michaela Seeger for performing the vast majority of the sequencing reactions. We thank J. den Dunnen for kindly providing the sCOGH2 cosmid vector and J. Nathans for the cDNA library. This work was supported by the Deutsche Forschungsgemeinschaft (G.v.D., Ro 389/16-3) and the Foundation Fighting Blindness, Inc., USA (R. Roepman). F.P.M.C. is recipient of a fellowship of the Royal Dutch Academy of Arts and Sciences.

REFERENCES

1 Jay,M. (1982) On the heredity of retinitis pigmentosa. Br. J. Ophthalmol., 66, 405-416. MEDLINE Abstract

2 Haim,M. (1993) Retinitis pigmentosa: problems associated with genetic classification. Clin. Genet., 44, 62-70. MEDLINE Abstract

3 Teague,P.W., Aldred,M.A., Jay,M., Dempster,M., Harrison,C., Carothers,A.D., Hardwick,L.J., Evans,H.J., Strain,L., Brock,D.J.H., Bundey,S., Jay,B., Bird,A.C., Bhattacharya,S.S. and Wright,A.F. (1994) Heterogeneity analysis in 40 X-linked retinitis pigmentosa families. Am. J. Hum. Genet., 55, 105-111. MEDLINE Abstract

4 Ott,J., Bhattacharya,S., Chen,J.D., Denton,M.J., Donald,J., Dubay,C., Farrar,G.J., Fishman,G.A., Frey,D., Gal,A., Humphries,P., Jay,L., Litt,M., Mächler,M., Musarella,M., Neugebauer,M., Nussbaum,R.L.,Terwilliger,J.D., Weleber,R.G., Wirth,B., Wong,F., Worton,R.G., and Wright,A.F. (1990) Localizing multiple X chromosome linked retinitis pigmentosa loci using multilocus homogeneity tests. Proc. Natl. Acad. Sci. USA, 87, 701-704 MEDLINE Abstract

5 Chen,J.D., Halliday,F., Keith,G., Sheffield,L., Dickinson,P., Gray,R., Constable,I. and Denton,M. (1989) Linkage heterogeneity between X-linked retinitis pigmentosa and a map of 10 RFLP loci. Am. J. Hum. Genet., 45, 401-411. MEDLINE Abstract

6 Roux,A.-F., Rommens,J., McDowell,C., Anson-Cartwright,L., Bell,S., Schappert,K., Fishman,G.A. and Musarella,M. (1994) Identification of a gene from Xp21 with similarity to the tctex-1 gene of the murine t complex. Hum. Mol. Genet., 3, 257-263. MEDLINE Abstract

7 Cremers,F.P.M., van de Pol,D.J.R., van Kerkhoff,L.P.M., Wieringa,B. and Ropers,H.H. (1990) Cloning of a gene that is rearranged in patients with choroideremia. Nature, 347, 674-677.

8 Berger,W., Meindl,A., van de Pol,T.J.R., Cremers,F.P.M., Ropers,H.H., Dörner,C., Monaco,A., Bergen,A.A.B., Lebo,R., Warburg,M., Zergollern,L., Lorenz,B., Gal,A., Bleeker-Wagemakers,E.M. and Meitinger,T. (1992) Isolation of a candidate gene for Norrie disease by positional cloning. Nature Genet., 1, 199-203. MEDLINE Abstract

9 Roepman,R., Bauer,D., Rosenberg,T., van Duijnhoven,G., van de Vosse,E., Platzer,M., Rosenthal,A., Ropers,H.-H., Cremers,F.P.M. and Berger,W. (1996) Identification of a gene disrupted by a microdeletion in a patient with X-linked retinitis pigmentosa (XLRP). Hum. Mol. Genet., 5, 827-833. MEDLINE Abstract

10 Program Manual for the Wisconsin Package (1994). Genetics Computer Group. Version 8. Madison, Wisconsin, USA

11 Bhattacharya,S.S., Wright,A.F., Clayton,J.F., Price,W.H., Phillips,C.I., McKeown,C.M.E., Jay,M., Bird,A.C., Pearson,P.L., Southern,E.M. and Evans,H.J. (1984) Close genetic linkage between X-linked retinitis pigmentosa and a restriction fragment length polymorphism identified by recombinant DNA probe L1.28. Nature, 309, 253-255. MEDLINE Abstract

12 Meindl,A., Carvalho,M.R.S., Herrmann,K., Lorenz,B., Achatz,H., Apfelstedt-Sylla,E., Wittwer,B., Ross,M. and Meitinger,T. (1995) A gene (SRPX) encoding a sushi-repeat-containing protein is deleted in patients with X-linked retinitis pigmentosa. Hum. Mol. Genet., 4, 2339-2346. MEDLINE Abstract

13 Ohtsubo,M., Kai,R., Furuno,N., Sekiguchi,T., Sekiguchi,M., Hayashida,H., Kuma,K., Miyata,T., Fukushige,S., Murotsu,T., Matsubara,K. and Nishimoto,T. (1987) Isolation and characterization of the active cDNA of the human cell cycle gene (RCC1) involved in the regulation of onset of chromosome condensation. Genes & Dev., 1, 585-593. MEDLINE Abstract

14 Nehrbass,U., Blobel,G. (1996) Role of the nuclear transport factor p10 in nuclear import. Science, 272, 120-122. MEDLINE Abstract

15 Boguski,M.S., McCormick,F. (1993) Proteins regulating ras and its relatives. Nature, 366, 643-654. MEDLINE Abstract

16 Seabra,M.C., Brown,M.S. and Goldstein,J.L. (1993) Retinal degeneration in choroideremia: deficiency of rab geranylgeranyl transferase. Science, 259, 377-381. MEDLINE Abstract

17 Moya,M., Roberts,D. and Novick,P. (1993) DSS4-1 is a dominant suppressor of sec4-8 that encodes a nucleotide exchange protein that aids Sec4p function. Nature, 361, 460-463. MEDLINE Abstract

18 Burton,J., Roberts,D., Montaldi,M., Novick,P. and De Camilli,P. (1993) A mammalian guanine-nucleotide-releasing protein enhances function of yeast secretory protein Sec4. Nature, 361, 464-467. MEDLINE Abstract

19 Datson,N.A., van de Vosse,E., Dauwerse,H.G., Bout,M., van Ommen,G.-J.B. and den Dunnen,J.T. (1996) Scanning for genes in large genomic regions: cosmid-based exon trapping of multiple exons in a single product. Nucleic Acids Res.,24, 1105-1111. MEDLINE Abstract

20 van Bokhoven,H., van den Hurk,J.A.J.M., Bogerd,L., Philipe,C., Gilgenkrantz,S., de Jong,P., Ropers,H.-H. and Cremers,F.P.M. (1994) Cloning and characterization of the human choroideremia gene. Hum. Mol. Genet., 3, 1041-1046. MEDLINE Abstract

21 Berger,W., van de Pol,D., Warburg,M., Gal,A., Bleeker-Wagemakers,L., de Silva,H., Meindl,A., Meitinger,T., Cremers,F. and Ropers,H.H. (1992) Mutations in the candidate gene for Norrie disease. Hum. Mol. Genet., 1, 461-465. MEDLINE Abstract

*To whom correspondence should be addressed

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Hypomorphic CEP290/NPHP6 mutations result in anosmia caused by the selective loss of G proteins in cilia of olfactory sensory neurons
PNAS, October 2, 2007; 104(40): 15917 - 15922.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
H. Prokisch, M. Hartig, R. Hellinger, T. Meitinger, and T. Rosenberg
A Population-Based Epidemiological and Genetic Study of X-Linked Retinitis Pigmentosa
Invest. Ophthalmol. Vis. Sci., September 1, 2007; 48(9): 4012 - 4018.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
I. Gosens, E. van Wijk, F. F.J. Kersten, E. Krieger, B. van der Zwaag, T. Marker, S. J.F. Letteboer, S. Dusseljee, T. Peters, H. A. Spierenburg, et al.
MPP1 links the Usher protein network and the Crumbs protein complex in the retina
Hum. Mol. Genet., August 15, 2007; 16(16): 1993 - 2003.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
M. Garcia-Hoyos, B. Garcia-Sandoval, D. Cantalapiedra, R. Riveiro, I. Lorda-Sanchez, M. J. Trujillo-Tiebas, M. Rodriguez de Alba, J. M. Millan, M. Baiget, C. Ramos, et al.
Mutational Screening of the RP2 and RPGR Genes in Spanish Families with X-Linked Retinitis Pigmentosa.
Invest. Ophthalmol. Vis. Sci., September 1, 2006; 47(9): 3777 - 3782.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
A Moore, E Escudier, G Roger, A Tamalet, B Pelosse, S Marlin, A Clement, M Geremek, B Delaisi, A-M Bridoux, et al.
RPGR is mutated in patients with a complex X linked phenotype combining primary ciliary dyskinesia and retinitis pigmentosa
J. Med. Genet., April 1, 2006; 43(4): 326 - 333.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
X. Shu, Z. Zeng, M. S. Eckmiller, P. Gautier, D. Vlachantoni, F. D. C. Manson, B. Tulloch, C. Sharpe, D. C. Gorecki, and A. F. Wright
Developmental and Tissue Expression of Xenopus laevis RPGR
Invest. Ophthalmol. Vis. Sci., January 1, 2006; 47(1): 348 - 356.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
R. Roepman, S. J. F. Letteboer, H. H. Arts, S. E. C. van Beersum, X. Lu, E. Krieger, P. A. Ferreira, and F. P. M. Cremers
Interaction of nephrocystin-4 and RPGRIP1 is disrupted by nephronophthisis or Leber congenital amaurosis-associated mutations
PNAS, December 20, 2005; 102(51): 18520 - 18525.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
P. A. Ferreira
Insights into X-linked retinitis pigmentosa type 3, allied diseases and underlying pathomechanisms
Hum. Mol. Genet., October 15, 2005; 14(suppl_2): R259 - R267.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
H. Khanna, T. W. Hurd, C. Lillo, X. Shu, S. K. Parapuram, S. He, M. Akimoto, A. F. Wright, B. Margolis, D. S. Williams, et al.
RPGR-ORF15, Which Is Mutated in Retinitis Pigmentosa, Associates with SMC1, SMC3, and Microtubule Transport Proteins
J. Biol. Chem., September 30, 2005; 280(39): 33580 - 33587.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
B. S. Pawlyk, A. J. Smith, P. K. Buch, M. Adamian, D.-H. Hong, M. A. Sandberg, R. R. Ali, and T. Li
Gene Replacement Therapy Rescues Photoreceptor Degeneration in a Murine Model of Leber Congenital Amaurosis Lacking RPGRIP
Invest. Ophthalmol. Vis. Sci., September 1, 2005; 46(9): 3039 - 3045.
[Abstract] [Full Text] [PDF]

Home page
 J HeredHome page
J. Aguirre-Hernandez and D. R. Sargan
Evaluation of Candidate Genes in the Absence of Positional Information: A Poor Bet on a Blind Dog!
J. Hered., September 1, 2005; 96(5): 475 - 484.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
N. D. Ebenezer, M. Michaelides, S. A. Jenkins, I. Audo, A. R. Webster, M. E. Cheetham, A. Stockman, E. R. Maher, J. R. Ainsworth, J. R. Yates, et al.
Identification of Novel RPGR ORF15 Mutations in X-linked Progressive Cone-Rod Dystrophy (XLCORD) Families
Invest. Ophthalmol. Vis. Sci., June 1, 2005; 46(6): 1891 - 1898.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
X. Lu, M. Guruju, J. Oswald, and P. A. Ferreira
Limited proteolysis differentially modulates the stability and subcellular localization of domains of RPGRIP1 that are distinctly affected by mutations in Leber's congenital amaurosis
Hum. Mol. Genet., May 15, 2005; 14(10): 1327 - 1340.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
X. Shu, A.M. Fry, B. Tulloch, F.D.C. Manson, J.W. Crabb, H. Khanna, A.J. Faragher, A. Lennon, S. He, P. Trojan, et al.
RPGR ORF15 isoform co-localizes with RPGRIP1 at centrioles and basal bodies and interacts with nucleophosmin
Hum. Mol. Genet., May 1, 2005; 14(9): 1183 - 1197.
[Abstract] [Full Text] [PDF]

Home page
 Br J OphthalmolHome page
S S Dandekar, N D Ebenezer, C Grayson, J P Chapple, C A Egan, G E Holder, S A Jenkins, F W Fitzke, M E Cheetham, A R Webster, et al.
An atypical phenotype of macular and peripapillary retinal atrophy caused by a mutation in the RP2 gene
Br J Ophthalmol, April 1, 2004; 88(4): 528 - 532.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
A Iannaccone, D K Breuer, X F Wang, S F Kuo, E M Normando, E Filippova, A Baldi, S Hiriyanna, C B MacDonald, F Baldi, et al.
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., November 1, 2003; 40(11): e118 - 118.
[Full Text] [PDF]

Home page
 IOVSHome page
K. R. Alexander, C. S. Barnes, and G. A. Fishman
ON-Pathway Dysfunction and Timing Properties of the Flicker ERG in Carriers of X-Linked Retinitis Pigmentosa
Invest. Ophthalmol. Vis. Sci., September 1, 2003; 44(9): 4017 - 4025.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
P. Castagnet, T. Mavlyutov, Y. Cai, F. Zhong, and P. Ferreira
RPGRIP1s with distinct neuronal localization and biochemical properties associate selectively with RanBP2 in amacrine neurons
Hum. Mol. Genet., August 1, 2003; 12(15): 1847 - 1863.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
I Zito, S M Downes, R J Patel, M E Cheetham, N D Ebenezer, S A Jenkins, S S Bhattacharya, A R Webster, G E Holder, A C Bird, et al.
RPGR mutation associated with retinitis pigmentosa, impaired hearing, and sinorespiratory infections
J. Med. Genet., August 1, 2003; 40(8): 609 - 615.
[Full Text]

Home page
 IOVSHome page
D.-H. Hong, B. Pawlyk, M. Sokolov, K. J. Strissel, J. Yang, B. Tulloch, A. F. Wright, V. Y. Arshavsky, and T. Li
RPGR Isoforms in Photoreceptor Connecting Cilia and the Transitional Zone of Motile Cilia
Invest. Ophthalmol. Vis. Sci., June 1, 2003; 44(6): 2413 - 2421.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
I. Bader, O. Brandau, H. Achatz, E. Apfelstedt-Sylla, M. Hergersberg, B. Lorenz, B. Wissinger, B. Wittwer, G. Rudolph, A. Meindl, et al.
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., April 1, 2003; 44(4): 1458 - 1463.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
D.-H. Hong and T. Li
Complex Expression Pattern of RPGR Reveals a Role for Purine-Rich Exonic Splicing Enhancers
Invest. Ophthalmol. Vis. Sci., November 1, 2002; 43(11): 3373 - 3382.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
T. A. Mavlyutov, H. Zhao, and P. A. Ferreira
Species-specific subcellular localization of RPGR and RPGRIP isoforms: implications for the phenotypic variability of congenital retinopathies among species
Hum. Mol. Genet., August 1, 2002; 11(16): 1899 - 1907.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
F. Bartolini, A. Bhamidipati, S. Thomas, U. Schwahn, S. A. Lewis, and N. J. Cowan
Functional Overlap between Retinitis Pigmentosa 2 Protein and the Tubulin-specific Chaperone Cofactor C
J. Biol. Chem., April 19, 2002; 277(17): 14629 - 14634.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
Z. Yang, N. S. Peachey, D. M. Moshfeghi, S. Thirumalaichary, L. Chorich, Y. Y. Shugart, K. Fan, and K. Zhang
Mutations in the RPGR gene cause X-linked cone dystrophy
Hum. Mol. Genet., March 1, 2002; 11(5): 605 - 611.
[Abstract] [Full Text] [PDF]

Home page
 J Exp BotHome page
B. Heras and B. K. Drobak
PARF-1: an Arabidopsis thaliana FYVE-domain protein displaying a novel eukaryotic domain structure and phosphoinositide affinity
J. Exp. Bot., March 1, 2002; 53(368): 565 - 567.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
U. Schwahn, N. Paland, S. Techritz, S. Lenzner, and W. Berger
Mutations in the X-linked RP2 gene cause intracellular misrouting and loss of the protein
Hum. Mol. Genet., May 1, 2001; 10(11): 1177 - 1183.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
R. Roepman, N. Bernoud-Hubac, D. E. Schick, A. Maugeri, W. Berger, H.-H. Ropers, F. P.M. Cremers, and P. A. Ferreira
The retinitis pigmentosa GTPase regulator (RPGR) interacts with novel transport-like proteins in the outer segments of rod photoreceptors
Hum. Mol. Genet., September 1, 2000; 9(14): 2095 - 2105.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
D. Sharon, G. A. P. Bruns, T. L. McGee, M. A. Sandberg, E. L. Berson, and T. P. Dryja
X-Linked Retinitis Pigmentosa: Mutation Spectrum of the RPGR and RP2 Genes and Correlation with Visual Function
Invest. Ophthalmol. Vis. Sci., August 1, 2000; 41(9): 2712 - 2721.
[Abstract] [Full Text]

Home page
 Hum Mol GenetHome page
C. J. Zeiss, K. Ray, G. M. Acland, and G. D. Aguirre
Mapping of X-linked progressive retinal atrophy (XLPRA), the canine homolog of retinitis pigmentosa 3 (RP3)
Hum. Mol. Genet., March 1, 2000; 9(4): 531 - 537.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
C. J. Zeiss, G. M. Acland, and G. D. Aguirre
Retinal Pathology of Canine X-linked Progressive Retinal Atrophy, the Locus Homologue of RP3
Invest. Ophthalmol. Vis. Sci., December 1, 1999; 40(13): 3292 - 3304.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
M. Linari, M. Ueffing, F. Manson, A. Wright, T. Meitinger, and J. Becker
The retinitis pigmentosa GTPase regulator, RPGR, interacts with the delta subunit of rod cyclic GMP phosphodiesterase
PNAS, February 16, 1999; 96(4): 1315 - 1320.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
D. Yan, P. K. Swain, D. Breuer, R. M. Tucker, W. Wu, R. Fujita, A. Rehemtulla, D. Burke, and A. Swaroop
Biochemical Characterization and Subcellular Localization of the Mouse Retinitis Pigmentosa GTPase Regulator (mRpgr)
J. Biol. Chem., July 31, 1998; 273(31): 19656 - 19663.
[Abstract] [Full Text] [PDF]

Home page
 Arch OphthalmolHome page
R. G. Weleber, N. S. Butler, W. H. Murphey, V. C. Sheffield, and E. M. Stone
X-linked Retinitis Pigmentosa Associated With a 2-Base Pair Insertion in Codon 99 of the RP3 Gene RPGR
Arch Ophthalmol, November 1, 1997; 115(11): 1429 - 1435.
[Abstract] [PDF]

Home page
 J. Biol. Chem.Home page
D.-H. Hong, G. Yue, M. Adamian, and T. Li
Retinitis Pigmentosa GTPase Regulator (RPGR)-interacting Protein Is Stably Associated with the Photoreceptor Ciliary Axoneme and Anchors RPGR to the Connecting Cilium
J. Biol. Chem., April 6, 2001; 276(15): 12091 - 12099.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
D.-H. Hong, B. S. Pawlyk, J. Shang, M. A. Sandberg, E. L. Berson, and T. Li
A retinitis pigmentosa GTPase regulator (RPGR)- deficient mouse model for X-linked retinitis pigmentosa (RP3)
PNAS, March 28, 2000; 97(7): 3649 - 3654.
[Abstract] [Full Text] [PDF]

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