Human Molecular Genetics, 2002, Vol. 11, No. 5 605-611
© 2002 Oxford University Press
Mutations in the RPGR gene cause X-linked cone dystrophy
1Cole Eye Institute, I-31, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA, 2Cleveland VA Medical Center and 3Department of Neurosciences, Case Western Reserve University, Cleveland, OH 44106, USA, 4William H. Havener Eye Center, Ohio State University, Columbus, OH 43210, USA and 5Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
Received January 22, 2002; Revised and Accepted February 8, 2002.
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSNOTE ADDED IN PROOFREFERENCES |
|---|
X-linked cone dystrophy is a type of hereditary retinal degeneration characterized by a progressive dysfunction of the day vision or photopic (cone) system with preservation of night vision or scotopic (rod) function. The disease presents with a triad of photophobia, loss of color vision and reduced central vision. This phenotype is distinct from retinitis pigmentosa (RP) in which there are prominent night and peripheral vision disturbances. X-linked cone dystrophy is a genetically heterogeneous disorder, with linkage to loci on Xp11.4–Xp21.1 (COD1, OMIM 304020) and Xq27 (COD2, OMIM 303800). COD1 maps to a region that harbors the RPGR gene, mutations in which account for >70% of patients with X-linked RP. The majority of these mutations reside in one purine-rich exon, ORF15, encoding 567 amino acids with a repetitive domain rich in glutamic acid residues. We mapped two families with X-linked cone dystrophy to the COD1 locus and identified two distinct mutations in ORF15 in the RPGR gene (ORF15+1343_1344delGG and ORF15+694_708del15) leading to a frame-shift and premature termination of translation in one case and a deletion of five amino acids in another. Consistent with expression of RPGR in rods and cones, our results show that mutations in RPGR, in addition to X-linked RP, can also cause cone-specific degeneration.
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSNOTE ADDED IN PROOFREFERENCES |
|---|
The cone dystrophies are a heterogeneous group of hereditary retinal degenerations characterized by progressive dysfunction of the photopic (cone-mediated) system, presenting with photophobia, loss of color vision and reduced central visual acuity. This phenotype is in contrast to that of retinitis pigmentosa (RP), which is characterized by abnormalities in scotopic (rod-mediated) functions, manifesting as night blindness and a decrease of peripheral vision. Cone dystrophy is genetically heterogeneous and may present as an autosomal dominant or X-linked recessive trait. Autosomal loci have been localized to 6p21.1 (COD3, OMIM 602093) (1), 6q25–q26 (OMIM 180020) and 17p12–13 (OMIM 601251) (2,3). In the case of COD3, mutations have been identified in the GUCA1A gene encoding GCAP1 (1,4,5), a Ca2+-binding protein involved in regulation of rod and cone phototransduction (6). X-linked cone dystrophy maps to Xp11.4–21.1 (COD1, OMIM 304020) (7–9) and Xq27 (COD2, OMIM 303800) (10).
X-linked RP is the most severe form of RP. Patients tend to present with night blindness and constriction of visual field during the third and fourth decades of life (11). In comparison, visual acuity and color vision can be normal in RP patients until advanced stages of the disease. X-linked RP is genetically heterogeneous, with loci localized to Xp11.2 (RP2), Xp21.1 (RP3) and Xp21.2–21.3 (RP6), Xp22 (RP23) and Xq26–27 (RP24) (http://www.sph.uth.tmc.edu/RetNet/disease.htm). Genes for RP2 and RP3 have been cloned (12–15). The RPGR (RP3) gene encodes a protein with homology to RCC1 (regulator of chromatin condensation-1), a guanine nucleotide exchange factor for the small GTPase Ran, a protein involved in nuclear trafficking. RPGR interacts with a protein termed RPGR-interacting protein (RPGRIP) (16–18). In addition, cones, as well as rods, degenerate in mice null for the RPGR gene (19). The RPGR gene was mutated in >70% of patients with X-linked RP and the majority of mutations resides in one purine-rich exon, ORF15, encoding 567 amino acids, with a repetitive domain of low sequence complexity with high glutamic acid and glycine content (15). ORF15 is preferentially expressed in mouse, bovine and human retina and is conserved in the pufferfish (Fugu rubripes), mouse, bovine and human (15). All mutations of ORF15 in RP3 patients were small nucleotide deletions or nonsense mutations in the 5'-end or the central portion of ORF15, resulting in premature truncation of translation (15,20,21). The high frequency of mutations within ORF15 compared with other parts of the same RPGR transcript suggested that it is a mutation hotspot (15).
Mutations in RPGR have been identified mainly in patients with the diagnosis of RP. We mapped two families with X-linked cone dystrophy to the COD1 locus and identified two distinct mutations in ORF15 in the RPGR gene (ORF+1343_1344delGG and ORF+694_708del15). The observation that mutations in RPGR can cause cone-specific degeneration indicates that in addition to a well established role for rod photoreceptors, RPGR also plays an important role in cone photoreceptors.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSNOTE ADDED IN PROOFREFERENCES |
|---|
Clinical evaluations
Clinical evaluations on two kindreds revealed an X-linked pattern of inheritance (Fig. 1). On the basis of the presence of photophobia, decreased visual acuity, color vision and macular abnormality, two of nine male individuals at risk for inheriting the disease in family A and two of four male individuals in family B were found to be affected. Decreased visual acuity and color vision appeared at ~45 years of age, followed by progressive macular atrophy (Fig. 2A–C). Figure 2D presents electroretinograms (ERGs) recorded under conditions that allow rod- and cone-mediated function to be compared. Rod-mediated responses recorded under dark-adapted conditions were clearly present in both patients from whom ERGs were obtained (Fig. 2D, upper two rows). The amplitude reduction observed in patient III:3 from family A may be attributed at least in part to the high myopia present in this individual (22). Consistent with this interpretation, dark adaptation recovery measured in this individual using a Goldmann–Weekers dark adaptometer proceeded with normal kinetics and achieved a final threshold that fell within the normal range (data not shown). In comparison, cone-mediated responses were markedly reduced in amplitude in both affected patients tested by ERG (Fig. 2D, lower two rows). Overall, these ERG results indicate a generalized loss of cone function, with preservation of rod function (Fig. 2D). Goldmann visual fields obtained from individual III:3 in family A and III:1 in family B showed that peripheral visual fields were preserved (data not shown). Taken together, clinical evaluations demonstrated that the disease phenotype in these two study families is that of a cone dystrophy.
|
|
Genetic analysis
An initial genotype analysis using polymorphic DNA markers DXS9896 and DXS6810 in family A demonstrated positive linkage to the COD1 locus. A two-point peak LOD score of 1.19 was obtained at
= 0 with marker DXS6810. In affected patients, the inheritance of a disease haplotype was concordant with the disease phenotype. Since RPGR is located in the proximity of COD1 and fell within the minimal genetic interval in this family, we performed mutational screening in the RPGR gene. Single-strand conformational polymorphism (SSCP) analysis followed by direct sequencing revealed a 2 bp deletion (ORF15+1343_1344delGG). This deletion resulted in a frame-shift, loss of a 120 amino acid long fragment at the C-terminus and synthesis of an aberrant peptide from amino acid 448 to 491 followed by a premature stop (Fig. 3A). We genotyped and then screened the RPGR gene in family B with X-linked cone dystrophy. We found a 15 bp deletion in nucleotides 694–708 of ORF15 resulting in elimination of five amino acids from 221 to 225 (Fig. 3B, ORF15+694_708del15). These changes segregated with the disease phenotype in each family, and were not found in 150 normal control subjects.
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSNOTE ADDED IN PROOFREFERENCES |
|---|
In this study we show that mutations in ORF15 of RPGR result in X-linked cone dystrophy (COD1) in two families. Several lines of evidence support the contention that a sequence change of ORF15+1343_1344delGG in RPGR is a pathogenic mutation. First, this change segregated with the disease phenotype in family A (Fig. 1). Secondly, this 2 bp deletion predicted a severe change, resulting in truncation of a 120 amino acid long fragment at the C-terminus. The 15 bp deletion (ORF15+694_708del15) was identified previously as a part of a compound mutation in conjunction with an ORF15+897G
T stop codon mutation in an X-linked RP family. In that case, the stop codon mutation eliminated more than half of the peptide coded by ORF15 (15), and we believe that this mutation was the primary cause of the RP phenotype. Consistent with the notion that ORF+694_708del15 is a pathogenic mutation causing cone dystrophy, rather than a polymorphism, this change segregated with the disease phenotype in family B (Fig. 1) and occurs in a highly conserved region of ORF15. Furthermore, neither ORF15+1343_1344delGG nor ORF15+694_708del15 were present in 150 normal control subjects in our population, in addition to being absent in 150 control chromosomes in a previous study (15). The function of RPGR is unknown. The presence of an RCC1 homology domain in the N-terminal domain of RPGR raises the possibility that RPGR may regulate intracellular transport in photoreceptors through a yet unidentified G protein. RPGR interacts with RPGRIP, a protein specifically expressed in the retina (16–18). Mutations in RPGRIP cause Leber’s congenital amaurosis (23,24).
Two lines of evidence support the notion that RPGR plays a role in cone photoreceptors: (i) RPGR is expressed in cone photoreceptors and (ii) knockout mice lacking the RPGR gene exhibit abnormal transport of cone opsin, in addition to defects in rhodopsin transport (19). In the late stage of retinal development, both rod and cone degeneration occur in RPGR knockout mice. Other support for primary cone disease as an important manifestation of RPGR mutations is provided by linkage of this site to X-linked dominant cone-rod degeneration (25) and by functional analysis of RP3 heterozygotes (26).
It is not clear why some RPGR mutations cause cone dystrophy while others cause RP. Mutations causing COD1 are either a truncating mutation located in the C-terminus of the RPGR protein or an in-frame five amino acid deletion in ORF15. In contrast, all RP3 mutations are truncating mutations that are clustered in the N-terminus or central portion of the ORF15, or in other exons that are located 5' to ORF15. While it seems reasonable to hypothesize that RPGR mutations restricted to the C-terminus may be associated with cone dystrophy whereas more severe terminating mutations are associated with RP, the mechanism(s) underlying this clinical heterogeneity remains to be elucidated. It is possible that different features of RPGR activity are required in rod and cone photoreceptors, such that cone photoreceptors are more sensitive to certain RPGR mutations than rod photoreceptors and vice versa. Alternatively, the C-terminus of RPGR may interact with a cone photoreceptor-specific component to confer cone specificity. Mutations in a single gene causing different phenotypes have been well documented in retinal diseases. For example, null mutations in the ABCA4 gene cause autosomal recessive RP, whereas missense mutations cause recessive Stargardt macular dystrophy (27,28). In another example, distinct mutations in the RDS gene are linked to dominant RP, dominant macular dystrophy, digenic RP (with ROM1) and dominant adult vitelliform macular dystrophy (29–31).
In the future, it will be important to develop a more complete understanding of the role(s) that RPGR plays in rod and cone photoreceptors. This information will provide the foundation for understanding the different effects that RPGR mutations may have on rods, to produce an RP phenotype, or on cones, to generate cone dystrophy.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSNOTE ADDED IN PROOFREFERENCES |
|---|
Subjects
Approval from the Institutional Review Board of the Cleveland Clinic Foundation was obtained for this study and informed consent was obtained from all patients. Seventeen individuals, including nine males at risk for inheriting cone dystrophy in the first Caucasian kindred, and eight individuals, including four males at risk for the disease, participated in the study. Both families are of northern European origin, as are the 150 normal control subjects.
Clinical investigations
A visual history was obtained from all patients and best-corrected visual acuities were assessed. Ophthalmoscopic examination was performed on all patients, and fluorescein angiography on three affected patients. Blood samples were obtained by venipuncture.
After initial dark adaptation, ERGs were recorded using a monopolar Burian–Allen contact lens electrode, to strobe flash stimuli presented within an LKC ganzfeld. Reference and ground leads were placed on the forehead and earlobe, respectively. The response was differentially amplified (band-pass: 0.3–500 Hz), averaged and stored using an LKC UTAS E-2000 signal-averaging system. Responses were initially recorded to flashes presented to the dark-adapted eye, using low intensity (–2.0 log cd s/m2) and high intensity (0.5 log cd s/m2) stimuli. A steady rod-desensitizing adapting field (1.5 log cd/m2) was then presented in the ganzfeld bowl. After a 7 min period of light adaptation (32), cone ERGs were recorded to 0.5 log cd s/m2 flashes presented at 0.7 Hz and 31 Hz.
Genetic linkage and mutation screening
DNA was extracted from blood samples and genetic linkage assessed using microsatellite markers DXS9896 and DXS6810 tightly linked to the COD1 and RPGR loci using established methods (33). An X-linked recessive mode of inheritance with full penetrance was used for LOD score computation. Disease allele frequency was set at 0.0001. Mutational screening of the 15 exons of the RPGR gene was performed by SSCP analysis followed by direct sequencing of PCR-amplified DNA fragments corresponding to each exon of the gene using established methods (13–15,34). PCR primers were designed according to published sequence (13,14) except for ORF15. The following primers were used to amplified overlapping fragments of ORF15: 5'-CATGGAAGGTGCAAGTGAGA-3' and 5'-TCCATCTCTTGGTTTCTTTCCTTC-3' (651 bp product); 5'-GCAGAACACTGGCAAGATGA-3' and 5'-TCTTCCCCTTCTTCCTCCC-3' (596 bp product); 5'-AGGAAGAGGAGGAGGGTGAG-3' and 5'-TTCTTCGCCTGTCTCCTGAT-3' (743 bp product); 5'-GAAGAGGAGGAAGGAGAAGGGGAG-3' and 5'-AGTGCCCGTTATATGCAAGG-3' (583 bp product). Direct sequencing was performed with the Taq Dyedeoxy Terminator Cycle Sequencing Kit (Beckman-Coulter, Fullerton, CA) according to the manufacturer’s instructions.
|
ACKNOWLEDGEMENTS |
|---|
We thank Drs Samuel Jacobson and Stephanie Hagstrom for advice and critical reading of the manuscript, Dr Samuel Jacobson for also providing patient samples, and Dr Hilel Lewis for supporting macular degeneration research at Cole Eye Institute. The authors are grateful to the patients and members of the families for their help with this study. This study was supported by grants from the NIH (K23 EY00401, K.Z.), the Steinbach Foundation (K.Z.), the Heed Ophthalmic Foundation (K.Z.), the Grant Ritter Fund (K.Z.), ARVO Alcon Research Grant (Z.Y.), the Ronald G. Michels Fellowship Foundation (D.M.M.) and the Medical Research Service, Department of Veterans Affairs (N.S.P.).
|
NOTE ADDED IN PROOF |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSNOTE ADDED IN PROOFREFERENCES |
|---|
An independent study has recently identified three different frame-shift ORF15 mutations in X-linked cone–rod dystrophy (COD1): one of these mutations is the same as we identified in our family (ORF15+1343_1344delGG) and was detected in two probably related families in that study (35).
|
FOOTNOTES |
|---|
+ To whom correspondence should be addressed at: Moran Eye Center, Department of Ophthalmology and Visual Science, University of Utah, 50 North Medical Drive, Salt Lake City, UT 84132, USA. Tel: +1 801 585 2019; Fax: +1 801 585 3501; Email: zhangk@ccf.org Present addresses: Zhenglin Yang, Sukanya Thirumalaichary, Keke Fan and Kang Zhang, Moran Eye Center, Department of Ophthalmology and Visual Science, University of Utah, 50 North Medical Drive, Salt Lake City, UT 84132, USA
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSNOTE ADDED IN PROOFREFERENCES |
|---|
1 Payne,A.M., Downes,S.M., Bessant,D.A., Taylor,R., Holder,G.E., Warren,M.J., Bird,A.C. and Bhattacharya,S.S. (1998) A mutation in guanylate cyclase activator 1A (GUCA1A) in an autosomal dominant cone dystrophy pedigree mapping to a new locus on chromosome 6p21.1. Hum. Mol. Genet., 7, 273–277.
2 Balciuniene,J., Johansson,K., Sandgren,O., Wachtmeister,L., Holmgren,G. and Forsman,K. (1995) A gene for autosomal dominant progressive cone dystrophy (CORD5) maps to chromosome 17p12-p13. Genomics, 30, 281–286.[ISI][Medline]
3 Small,K.W., Syrquin,M., Mullen,L. and Gehrs,K. (1996) Mapping of autosomal dominant cone degeneration to chromosome 17p. Am. J. Ophthalmol., 121, 13–18.[ISI][Medline]
4
Downes,S.M., Holder,G.E., Fitzke,F.W., Payne,A.M., Warren,M.J., Bhattacharya,S.S. and Bird,A.C. (2001) Autosomal dominant cone and cone-rod dystrophy with mutations in the guanylate cyclase activator 1A gene-encoding guanylate cyclase activating protein-1. Arch. Ophthalmol., 119, 96–105.
5 Wilkie,S.E., Li,Y., Deery,E.C., Newbold,R.J., Garibaldi,D., Bateman,J.B., Zhang,H., Lin,W., Zack,D.J., Bhattacharya,S.S. et al. (2001) Identification and functional consequences of a new mutation (E155G) in the gene for GCAP1 that causes autosomal dominant cone dystrophy. Am. J. Hum. Genet., 69, 471–480.[ISI][Medline]
6 Palczewski,K., Polans,A.S., Baehr,W. and Ames,J.B. (2000) Ca(2+)-binding proteins in the retina: structure, function, and the etiology of human visual diseases. Bioessays, 22, 337–350.[ISI][Medline]
7 Bartley,J., Gies,C. and Jacobson,D. (1989) Cone dystrophy (X-linked) (COD1) maps between DXS7(L1.28) and DXS206(XJ1.1) and is linked to DXS84(754). Cytogenet. Cell Genet., 51, 959.
8 Hong,H.K., Ferrell,R.E. and Gorin,M.B. (1994) Clinical diversity and chromosomal localization of X-linked cone dystrophy (COD1). Am. J. Hum. Genet., 55, 1173–1181.[ISI][Medline]
9 Bergen,A.A., Meire,F., ten Brink,J., Schuurman,E.J., van Ommen,G.J. and Delleman,J.W. (1993) Additional evidence for a gene locus for progressive cone dystrophy with late rod involvement in Xp21.1-p11.3. Genomics, 18, 463–464.[ISI][Medline]
10 Bergen,A.A.B. and Pinckers,A.J.L.G. (1997) Localization of a novel X-linked progressive cone dystrophy gene to Xq27: evidence for genetic heterogeneity. Am. J. Hum. Genet., 60, 1468–1473.[ISI][Medline]
11
Bird,A.C. (1975) X-linked retinitis pigmentosa. Br. J. Ophthalmol., 59, 177–199.
12 Schwahn,U., Lenzner,S., Dong,J., Feil,S., Hinzmann,B., van Duijnhoven,G., Kirschner,R., Hemberger,M., Bergen,A.A., Rosenberg,T. et al. (1998) Positional cloning of the gene for X-linked retinitis pigmentosa 2. Nat. Genet., 19, 327–332.[ISI][Medline]
13 Meindl,A., Dry,K., Herrmann,K., Manson,F., Ciccodicola,A., Edgar,A., Carvalho,M.R., Achatz,H., Hellebrand,H., Lennon,A. et al. (1996) A gene (RPGR) with homology to the RCC1 guanine nucleotide exchange factor is mutated in X-linked retinitis pigmentosa (RP3). Nat. Genet., 13, 35–42.[ISI][Medline]
14
Roepman,R., van Duijnhoven,G., Rosenberg,T., Pinckers,A.J., Bleeker-Wagemakers,L.M., Bergen,A.A., Post,J., Beck,A., Reinhardt,R., Ropers,H.H., Cremers,F.P. and Berger,W. (1996) Positional cloning of the gene for X-linked retinitis pigmentosa 3: homology with the guanine-nucleotide-exchange factor RCC1. Hum. Mol. Genet., 5, 1035–1041.
15 Vervoort,R., Lennon,A., Bird,A.C., Tulloch,B., Axton,R., Miano,M.G., Meindl,A., Meitinger,T., Ciccodicola,A. and Wright,A.F. (2000) Mutational hot spot within a new RPGR exon in X-linked retinitis pigmentosa. Nat. Genet., 25, 462–466.[ISI][Medline]
16
Boylan,J.P. and Wright,A.F. (2000) Identification of a novel protein interacting with RPGR. Hum. Mol. Genet., 9, 2085–2093.
17
Roepman,R., Bernoud-Hubac,N., Schick,D.E., Maugeri,A., Berger,W., Ropers,H.H., Cremers,F.P. and Ferreira,P.A. (2000) The retinitis pigmentosa GTPase regulator (RPGR) interacts with novel transport-like proteins in the outer segments of rod photoreceptors. Hum. Mol. Genet., 9, 2095–2105.
18
Hong,D.H., Yue,G., Adamian,M. and Li,T. (2001) Retinitis pigmentosa GTPase regulator (RPGRr)-interacting protein is stably associated with the photoreceptor ciliary axoneme and anchors RPGR to the connecting cilium. J. Biol. Chem., 276, 12091–12099.
19
Hong,D.H., Pawlyk,B.S., Shang,J., Sandberg,M.A., Berson,E.L. and Li,T. (2000) A retinitis pigmentosa GTPase regulator (RPGR)-deficient mouse model for X-linked retinitis pigmentosa (RP3). Proc. Natl Acad. Sci. USA, 97, 3649–3654.
20 Buraczynska,M., Wu,W., Fujita,R., Buraczynska,K., Phelps,E., Andreasson,S., Bennett,J., Birch,D.G., Fishman,G.A., Hoffman,D.R. et al. (1997) Spectrum of mutations in the RPGR gene that are identified in 20% of families with X-linked retinitis pigmentosa. Am. J. Hum. Genet., 61, 1287–1292.[ISI][Medline]
21
Sharon,D., Bruns,G.A., McGee,T.L., Sandberg,M.A., Berson,E.L. and Dryja,T.P. (2000) X-linked retinitis pigmentosa: mutation spectrum of the RPGR and RP2 genes and correlation with visual function. Invest. Ophthalmol. Vis. Sci., 41, 2712–2721.
22 Chen,J.-F., Elsner,A.E., Burns,S.A., Hansen,R.M., Lou,P.L., Kwong,K.K. and Fulton,A.B. (1992) The effect of eye shape on retinal responses. Clin. Vision Sci., 7, 521–530.
23 Gerber,S., Perrault,I., Hanein,S., Barbet,F., Ducroq,D., Ghazi,I., Martin-Coignard,D., Leowski,C., Homfray,T., Dufier,J.L. et al. (2001) Complete exon–intron structure of the RPGR-interacting protein (RPGRIP1) gene allows the identification of mutations underlying Leber congenital amaurosis. Eur. J. Hum. Genet., 9, 561–571.[ISI][Medline]
24 Dryja,T.P., Adams,S.M., Grimsby,J.L., McGee,T.L., Hong,D.H., Li,T., Andreasson,S. and Berson,E.L. (2001) Null RPGRIP1 alleles in patients with Leber congenital amaurosis. Am. J. Hum. Genet., 68, 1295–1298.[ISI][Medline]
25 Mears,A.J., Hiriyanna,S., Vervoort,R., Yashar,B., Gieser,L., Fahrner,S., Daiger,S.P., Heckenlively,J.R., Sieving,P.A., Wright,A.F. et al. (2000) Remapping of the RP15 locus for X-linked cone-rod degeneration to Xp11.4-p21.1, and identification of a de novo insertion in the RPGR exon ORF15. Am. J. Hum. Genet., 67, 1000–1003.[ISI][Medline]
26
Jacobson,S.G., Buraczynska,M., Milam,A.H., Chen,C., Jarvalainen,M., Fujita,R., Wu,W., Huang,Y., Cideciyan,A.V. and Swaroop,A. (1997) Disease expression in X-linked retinitis pigmentosa caused by a putative null mutation in the RPGR gene. Invest. Ophthalmol. Vis. Sci., 38, 1983–1997.
27 Martinez-Mir,A., Paloma,E., Allikmets,R., Ayuso,C., del Rio,T., Dean,M., Vilageliu,L., Gonzalez-Duarte,R. and Balcells,S. (1998) Retinitis pigmentosa caused by a homozygous mutation in the Stargardt disease gene ABCR. Nat. Genet., 18, 11–12.[ISI][Medline]
28 Allikmets,R., Singh,N., Sun,H., Shroyer,N.F., Hutchinson,A., Chidambaram,A., Gerrard,B., Baird,L., Stauffer,D., Peiffer,A. et al. (1997) A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat. Genet., 15, 236–246.[ISI][Medline]
29 Wells,J., Wroblewski,J., Keen,J., Inglehearn,C., Jubb,C., Eckstein,A., Jay,M., Arden,G., Bhattacharya,S., Fitzke,F. et al. (1993) Mutations in the human retinal degeneration slow (RDS) gene can cause either retinitis pigmentosa or macular dystrophy. Nat. Genet., 3, 213–218.[ISI][Medline]
30 Nichols,B.E., Sheffield,V.C., Vandenburgh,K., Drack,A.V., Kimura,A.E. and Stone,E.M. (1993) Butterfly-shaped pigment dystrophy of the fovea caused by a point mutation in codon 167 of the RDS gene. Nat. Genet., 3, 202–207.[ISI][Medline]
31 Weleber,R.G., Carr,R.E., Murphey,W.H., Sheffield,V.C. and Stone,E.M. (1993) Phenotypic variation including retinitis pigmentosa, pattern dystrophy, and fundus flavimaculatus in a single family with a deletion of codon 153 or 154 of the peripherin/RDS gene. Arch. Ophthalmol., 111, 1531–1542.[Abstract]
32 Peachey,N.S., Alexander,K.R., Fishman,G.A. and Derlacki,D.J. (1989) Properties of the human cone system electroretinogram during light adaptation. Appl. Opt., 28, 1145–1150.
33 Kniazeva,M., Chiang,M.F., Morgan,B., Anduze,A.L., Zack,D.J., Han,M. and Zhang,K. (1999) A new locus for autosomal dominant stargardt-like disease maps to chromosome 4. Am. J. Hum. Genet., 64, 1394–1399.[ISI][Medline]
34 Zhang,K., Kniazeva,M., Han,M., Li,W., Yu,Z., Yang,Z., Li,Y., Metzker,M.L., Allikmets,R., Zack,D.J. et al. (2001) A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy. Nat. Genet., 27, 89–93.[ISI][Medline]
35 Demirci,F.Y.K., Rigatti,B.W., Wen,G., Radak,A.L., Mah,T.S., Baic,C.L., Traboulsi,E.I., Alitalo,T., Ramser,J. and Gorin,M.B. (2002) X-linked cone–rod dystrophy (COD1): identification of mutations in RPGR exon ORF15. Am. J. Hum. Genet., in press.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Walia, G. A. Fishman, A. Swaroop, K. E. H. Branham, M. Lindeman, M. Othman, and R. G. Weleber Discordant Phenotypes in Fraternal Twins Having an Identical Mutation in Exon ORF15 of the RPGR Gene Arch Ophthalmol, March 1, 2008; 126(3): 379 - 384. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Fu, D. Garland, Z. Yang, D. Shukla, A. Rajendran, E. Pearson, E. M. Stone, K. Zhang, and E. A. Pierce The R345W mutation in EFEMP1 is pathogenic and causes AMD-like deposits in mice Hum. Mol. Genet., October 15, 2007; 16(20): 2411 - 2422. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z.-B. Jin, F. Gu, X. Ma, and N. Nao-i Identification of a Novel RPGR Exon ORF15 Mutation in a Family With X-linked Retinitis Pigmentosa Arch Ophthalmol, October 1, 2007; 125(10): 1407 - 1412. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Duncan, Y. Zhang, J. Gandhi, C. Nakanishi, M. Othman, K. E. H. Branham, A. Swaroop, and A. Roorda High-Resolution Imaging with Adaptive Optics in Patients with Inherited Retinal Degeneration Invest. Ophthalmol. Vis. Sci., July 1, 2007; 48(7): 3283 - 3291. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R Jalkanen, M Mantyjarvi, R Tobias, J Isosomppi, E-M Sankila, T Alitalo, and N T Bech-Hansen X linked cone-rod dystrophy, CORDX3, is caused by a mutation in the CACNA1F gene J. Med. Genet., August 1, 2006; 43(8): 699 - 704. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
X. Lu and P. A. Ferreira Identification of Novel Murine- and Human-Specific RPGRIP1 Splice Variants with Distinct Expression Profiles and Subcellular Localization Invest. Ophthalmol. Vis. Sci., June 1, 2005; 46(6): 1882 - 1890. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
M. Michaelides, I. A. Aligianis, J. R. Ainsworth, P. Good, J. D. Mollon, E. R. Maher, A. T. Moore, and D. M. Hunt Progressive Cone Dystrophy Associated with Mutation in CNGB3 Invest. Ophthalmol. Vis. Sci., June 1, 2004; 45(6): 1975 - 1982. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
D.-H. Hong, B. S. Pawlyk, M. Adamian, and T. Li Dominant, Gain-of-Function Mutant Produced by Truncation of RPGR Invest. Ophthalmol. Vis. Sci., January 1, 2004; 45(1): 36 - 41. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Akimoto, E. Filippova, P. J. Gage, X. Zhu, C. M. Craft, and A. Swaroop Transgenic Mice Expressing Cre-Recombinase Specifically in M- or S-Cone Photoreceptors Invest. Ophthalmol. Vis. Sci., January 1, 2004; 45(1): 42 - 47. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
R Jalkanen, F Y Demirci, H Tyynismaa, T Bech-Hansen, A Meindl, M Peippo, M Mantyjarvi, M B Gorin, and T Alitalo A new genetic locus for X linked progressive cone-rod dystrophy J. Med. Genet., June 1, 2003; 40(6): 418 - 423. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||