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Ophthalmic Molecular Genetics |

Identification of a Novel RPGR Exon ORF15 Mutation in a Family With X-linked Retinitis Pigmentosa FREE

Zi-Bing Jin, MD, PhD; Feng Gu, PhD; Xu Ma, PhD; Nobuhisa Nao-i, MD
[+] Author Affiliations

Author Affiliations: Department of Ophthalmology and Visual Science, University of Miyazaki, Miyazaki, Japan (Drs Jin and Nao-i); and Department of Genetics, National Research Institute for Family Planning (Drs Gu and Ma) and Department of Reproductive Genetics, World Health Organization Collaborative Center for Research in Human Reproduction (Dr Ma), Beijing, China. Dr Jin is now with the Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Kobe, Japan.


Section Editor: Janey L. Wiggs, MD, PhD

More Author Information
Arch Ophthalmol. 2007;125(10):1407-1412. doi:10.1001/archopht.125.10.1407.
Text Size: A A A
Published online

Objective  To investigate the phenotypic and genotypic characteristics of a novel mutation associated with X-linked retinitis pigmentosa (XLRP).

Methods  Six individuals in a family with XLRP were recruited, and clinical examinations were performed. All of the members were genotyped with microsatellite markers at loci that were considered to be associated with XLRP. The retinitis pigmentosa GTPase regulator gene (RPGR) was comprehensively screened using direct polymerase chain reaction sequencing.

Results  Genotyping analysis showed that the affected individuals in the family shared a common haplotype with selected markers. The patients demonstrated severe retinal degenerative phenotypes consistent with XLRP. Mutational screening of RPGR demonstrated a novel mutation, g.ORF15 + 1232_1233delGG.

Conclusions  We identified a novel mutation in the 3′ end of a highly repetitive region of exon open reading frame 15 (ORF15) and documented the detailed phenotypes of the patients with XLRP with the mutation. The clinical phenotype was consistent with XLRP, supporting the observation that the mutations in the 3′ end of the ORF15 coding sequence give rise to XLRP.

Clinical Relevance  The mutation in the 3′ end of the ORF15 coding sequence can lead to a spectrum of phenotypes, and the cone-predominant phenotype-related mutations can be located irregularly in exon ORF15.

Figures in this Article

Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous disease with progressive degeneration of retinal photoreceptors characterized by night blindness, progressive loss of peripheral vision, and typically the appearance of bone spicules in the retina. X-linked RP (XLRP) is the most severe among different heritable forms of RP. In affected males, rod and cone dysfunctions begin in early childhood and functions deteriorate rapidly. Female carriers display a wide spectrum of clinical features, ranging from normal to severe manifestations.

To date, more than 32 genes responsible for RP have been cloned. Two of the most prevalent genes, the retinitis pigmentosa GTPase regulator gene (RPGR) and the retinitis pigment 2, X-linked gene (RP2), are known to be defective in 60% to 90% and 10% to 20% of families with XLRP, respectively.14 The newly identified exon open reading frame 15 (ORF15), spanning a 1706–base pair (bp) coding sequence, is a mutation hot spot for XLRP.5 More recently, ORF15 mutations have been identified in X-linked cone-rod dystrophy (XLCORD).69 A study10 involving comprehensive molecular screening of a large number of families with XLRP and several families with XLCORD identified a number of mutations. The investigators assumed that mutations close to downstream of ORF15 implicate the early preferential loss of cone function with slight-to-moderate loss of rod function and downstream mutations are responsible for XLCORD. A recent study9 reported 2 nonsense mutations located at the 3′ end of the highly repetitive region (codons 143-468) of ORF15 (codons 365 and 392), supporting the idea that mutations toward the 3′ end of the highly repetitive region may cause cone-predominant dysfunction. Thus far, RPGR exon ORF15 is the only known gene responsible for XLCORD. A number of mutations in the 3′ end of the ORF15 coding sequence have been identified in families with XLRP, but few detailed phenotypic descriptions have been documented.11 Such data are important both for studying the genotype-phenotype correlation and for elucidating the distribution and contribution of the ORF15 mutations.

The aim of this study was to identify the mutation in a specific family with XLRP and to characterize the phenotypic changes in patients with the mutation. Through genotyping and mutational analysis, a novel mutation located at the 3′ end of the highly repetitive region of exon ORF15 was identified and the genotype-phenotype correlation was determined.

FAMILY ASCERTAINMENT

This study followed the tenets of the Declaration of Helsinki. The protocol of this study was approved by the ethics committee of Miyazaki Medical College. Informed consent was obtained from all of the family members participating in this study. The study consisted of 6 members who were recruited for DNA testing (Figure 1). Blood samples were collected and genomic DNA was extracted by standard protocols (DNA Extractor WB Kit; Wako Pure Chemical Industries, Ltd, Osaka, Japan). Clinical examinations included routine ophthalmic examinations, Goldmann perimetry, electroretinography (ERG), and color fundus photography. The diagnosis of RP was confirmed by ophthalmologists (Z.-B.J. and N.N.). There was no history of other ocular or systemic abnormalities in the family.

Place holder to copy figure label and caption
Figure 1.

Pedigree of the family with X-linked retinitis pigmentosa and segregation analysis of the microsatellite at Xp11.3-11.4. Closed symbols indicate subjects with retinitis pigmentosa; open symbols, unaffected individuals; squares, males; circles, females; dotted circles, female carriers; bars over the symbols, personally examined subjects; and arrow, propositus.

Graphic Jump Location
GENOTYPING

Genotyping using microsatellite markers (DXS1068, DXS8025, DXS6810, DXS8054, and G10578) involved polymerase chain reaction amplification of the microsatellite region following standard methods and measurement of the size of the amplified fragment. The oligonucleotide primer sequences and the order of the markers were taken from NCBI and ENSEMBL databases. The genotypes were obtained by silver stain and manual inspection. The pedigree and haplotypes were constructed by Cyrillic software version 2.1 (Cyrillic Software, Oxfordshire, England).

The coding fragments and intron-exon boundaries of RPGR, including exons 1 to 19, exon 15a, and ORF15, were amplified by polymerase chain reactions and sequenced according to the protocols described previously.1215 Nucleotide positions were based on GenBank sequence AF286472. The DNA for 118 normal subjects was screened as described previously.14

CLINICAL EVALUATIONS

Two affected males and 2 obligate carriers in the 3-generation family were assessed. The clinical data are summarized in Table 1.

Table Graphic Jump LocationTable 1. Summary of Clinical Findings for the Family With X-linked Retinitis Pigmentosa

The propositus (III:1) was an 18-year-old man. He noticed night blindness and blurred vision at age 13 years but did not go to the hospital then. He visited our university hospital for examination when he was aged 18 years. Ophthalmologic examinations revealed pigmentation in midperipheral fundi (Figure 2A). On his most recent visit (when he was aged 19 years), Goldmann perimetry showed paracentral scotoma (isopter II-4e and III-4e) and depression of threshold values (isopter II-4e, 15°; III-4e, 30°; and V-4e, 45°). Both maximum-flash ERG and 30-Hz flicker ERG showed extinguished responses (Figure 2A). The propositus's mother (II:3), a heterozygous woman aged 39 years, did not have night blindness. She had high myopia with best-corrected visual acuity of 0.8 OU, and the fundus examination showed chorioretinal thinning, myopic optic discs, and peripapillary atrophy, which were consistent with high myopia. Few spicule formations were observed in the peripheral fundi (Figure 2B). The ERG showed a reduced response (Figure 2B). The propositus's grandfather (I:3), aged 66 years, had night blindness and severe myopia from childhood. Phacectomy was performed on one of his eyes at age 18 years and on the other eye at age 66 years because of high myopia. He had very poor visual acuity and severe myopic fundi with extensive chorioretinal atrophy as well as midperipheral pigmentation (Figure 2C). The ERG showed a distinguished response (Figure 2C). Goldmann perimetry results were unrecordable because of the low vision. The propositus's younger sister (III:2) noticed night blindness at age 17 years. Fundus examination showed bilateral chorioretinal atrophy that was consistent with high myopia (Figure 2D). The ERG showed a severely reduced response (Figure 2D) and the visual field was slightly reduced. The propositus's father and youngest sister had no symptoms or signs of RP, and their ERG and Goldmann perimetry results were normal.

Place holder to copy figure label and caption
Figure 2.

Representative fundus photographs and electroretinography (ERG) results of individuals with X-linked retinitis pigmentosa, including the propositus (III:1) (A), the carrier II:3 (B), the patient I:3 (C), and the carrier III:2 (D).

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GENOTYPING AND MUTATIONAL ANALYSIS

Haplotype analysis showed that the affected individuals in the family shared a common haplotype with 5 markers (Figure 1). Direct polymerase chain reaction sequencing of affected individuals identified a 2-bp deletion at positions 1232 and 1233 (Figure 3) in exon ORF15, which was predicted to create an early termination at position 492 (Gly411fsTer492). The ORF15Gly411fsTer492 refers to a frameshift mutation in which Gly411 is the first amino acid altered and the termination of the ORF is at residue 492. The mutation was cosegregated with affected individuals in the family and was not observed in any of the unaffected family members or the group of normal controls.

Place holder to copy figure label and caption
Figure 3.

Sequence chromatograms. The normal alleles (A) were compared with the hemizygous (B) and heterozygous (C) mutations identified in the study. The chromatograms are shown as the reverse sequence. The square indicates the deleted 2 nucleotides.

Graphic Jump Location

RPGR accounts for up to 20% of all cases of RP,16 which is higher than any other RP locus. Mutations of RPGR are responsible for nonsystematic or systematic XLRP, XLCORD, X-linked cone dystrophy, and X-linked recessive atrophic macular degeneration. To date, at least 97 different mutations in exon ORF15 have been reported.17 However, the precise role of ORF15 is still unclear. Studying the genotype-phenotype correlation can elucidate the expressivity and penetration of the phenotype in the patient with a specific mutation in RPGR. By evaluating 2 different dog strains with mutations in different locations of ORF15, Zhang et al18 found that mutations toward the 3′ end of ORF15 and with subsequent shorter abnormal amino acid sequences produce higher retention of rod function and hence milder RP phenotypes. Sharon et al10 also proposed a hypothesis that mutations downstream of codon 445 in ORF15 strongly implicate the early preferential loss of cone function with slight-to-moderate loss of rod function. Consistent with their findings, 4 of the ORF15 mutations identified in families with XLCORD or X-linked cone dystrophy were located downstream of codon 445 of ORF15.6,7,10 A recent study reported 2 nonsense mutations (codons 365 and 392) located in the 3′ end of the ORF15 highly repetitive stretch, indicating that mutations toward the 3′ end (downstream of codon 365) of the highly repetitive region may cause cone-predominant dysfunction.9 It is noted that there are more XLRP mutations in the 3′ end of the highly repetitive stretch of ORF15 than XLCORD mutations, and the region downstream of codon 445 harbors more XLCORD mutations than XLRP mutations. Hypothetically setting codon 365 as a point of demarcation, there were at least 24 mutations downstream of codon 365 that were identified in patients diagnosed with XLRP. Even setting codon 445 as a point of demarcation, 10 different mutations downstream of codon 445 had been reported, and this most 3′ coding region still harbors 4 mutations for confirmed XLRP and 1 mutation responsible for both XLRP and XLCORD. We retrospectively summarized the mutations downstream of codon 365 (nucleotide position 1095) from the previous studies (Table 2). Of the 32 mutations, 7 were reported in 8 unrelated families with XLCORD and 1 mutation was reported in a family with X-linked recessive atrophic macular degeneration8 that was subsequently suspected by other investigators to have had XLCORD.9 In addition, a mutation (g.ORF15 + 1563-1566delAAGT) very close to the 3′ end of the ORF15 coding sequence was reported in a family with XLRP,22 but the investigators admitted that the patients had cone-rod dystrophy in their records. Most recently, Pelletier et al19 reported the mutation g.ORF15 + 1641_1642delAA closest to the 3′ end of ORF15 in a family with XLCORD. Interestingly, the mutation of ORF15 + 1339-1340delAG was detected in 3 families with XLCORD6,10,20 as well as in 1 family with XLRP.20 The remaining 24 mutations, including the mutation identified in our study, were reported in 32 unrelated families with XLRP.57,10,11,14,1922 It is worthwhile to note that, to our knowledge, few detailed phenotypes were documented in these families with XLRP with mutations at the 3′ end of the coding sequence of exon ORF15.11

Table Graphic Jump LocationTable 2. Summary of the Mutations Downstream of Codon 365 in Open Reading Frame 15

The detailed phenotypes of the family in our study are consistent with XLRP. The affected males had night blindness at early ages and experienced progressive deterioration in central vision with no apparent macular degeneration in their fundi. The 2 male patients had typical RP symptoms and extinguished ERG responses (on both maximum-flash and 30-Hz flicker ERG), which were consistent with previously reported XLRP cases that had severe retinal degeneration with both rod and cone affected.13,23 It is well known that female carriers have a wide spectrum of phenotypes ranging from normal to severe. In our study, the 2 carriers were highly myopic, a known characteristic of XLRP carriers. Both showed reduced ERG responses, and Goldmann perimetry testing showed reduction in individual III:2 (the data for II:3 were not available). It appears that the patients and carriers with this mutation have both rod and cone dysfunctions, which is in contrast to the previous hypothesis proposed by Sharon et al.10 Because the numbers of families with XLCORD or X-linked cone dystrophy were small and a limited number of families with XLRP with mutations in the 3′ end of the exon ORF15 coding sequence were described, further studies are required to elucidate the significance of the mutation location and distribution. Both RP and cone-rod dystrophy are very heterogeneous in clinical symptoms. Because some cases of cone-rod dystrophy may have only minor macular retinal pigment epithelium atrophy without typical bull's-eye maculopathy and may show both cone and rod involvements in ERGs, which also appear in some RP cases (especially in XLRP with rapid deterioration and severe degeneration of both rods and cones), the similarity in symptoms leads to an indecisive diagnosis. More definite clinical diagnosis and classification are necessary for a differential diagnosis of XLCORD and for elucidating the role of ORF15 in cone and rod involvements.

We have identified a novel mutation in a family with XLRP and have documented the clinical manifestations. The clinical findings are consistent with previous reports of XLRP phenotypes associated with mutations in RPGR, leading us to speculate that the mutation 3′ toward the highly repetitive stretch of ORF15 or in the 3′ end of the ORF15 coding sequence may be the cause of XLRP as well as XLCORD, and the mutation in the 3′ end of ORF15 can lead to a spectrum of phenotypes. Our findings are consistent with the previous studies listed in Table 2 that have suggested the tendency of XLRP mutations to cluster in the highly repetitive region and support the observation that RPGR exon ORF15 mutations (including those that are located at the 3′ end of the exon ORF15 coding sequence) can cause different phenotypes. The summarized ORF15 mutations downstream from codon 365 (Table 2) also clearly suggest that the cone-predominant phenotype-related mutations can be located irregularly in the exon ORF15 coding sequence, and the number of families is not sufficient for a meaningful conclusion given the rare occurrence of this phenotype. The detailed phenotypes of patients with the mutation close to the 3′ end of the ORF15 coding sequence may be helpful in comparing the XLRP with the increasing XLCORD caused by ORF15 mutations and in establishing the significance of the mutation distribution and genotype-phenotype correlation. Further studies exploring the correspondence between mutations and phenotypes are required to gain insight into the pathogenesis of XLRP and XLCORD.

Correspondence: Nobuhisa Nao-i, MD, Department of Ophthalmology & Visual Science, Faculty of Medicine, University of Miyazaki, Kihara 5200, Kiyotake, Miyazaki 889-1692, Japan (naoi@fc.miyazaki-u.ac.jp).

Submitted for Publication: September 26, 2006; final revision received February 9, 2007; accepted February 28, 2007.

Financial Disclosure: None reported.

Funding/Support: This work was supported in part by Grant-in-Aid for Scientific Research (C) 17591843 from the Japan Society for the Promotion of Science.

Bergen  AAVan den Born  LISchuurman  EJ  et al.  Multipoint linkage analysis and homogeneity tests in 15 Dutch X-linked retinitis pigmentosa families. Ophthalmic Genet 1995;16 (2) 63- 70
PubMed
Fujita  RBuraczynska  MGieser  L  et al.  Analysis of the RPGR gene in 11 pedigrees with the retinitis pigmentosa type 3 genotype: paucity of mutations in the coding region but splice defects in two families. Am J Hum Genet 1997;61 (3) 571- 580
PubMed
Musarella  MAAnson-Cartwright  LLeal  SM  et al.  Multipoint linkage analysis and heterogeneity testing in 20 X-linked retinitis pigmentosa families. Genomics 1990;8 (2) 286- 296
PubMed
Teague  PWAldred  MAJay  M  et al.  Heterogeneity analysis in 40 X-linked retinitis pigmentosa families. Am J Hum Genet 1994;55 (1) 105- 111
PubMed
Vervoort  RLennon  ABird  AC  et al.  Mutational hot spot within a new RPGR exon in X-linked retinitis pigmentosa. Nat Genet 2000;25 (4) 462- 466
PubMed
Demirci  FYRigatti  BWWen  G  et al.  X-linked cone-rod dystrophy (locus COD1): identification of mutations in RPGR exon ORF15. Am J Hum Genet 2002;70 (4) 1049- 1053
PubMed
Yang  ZPeachey  NSMoshfeghi  DM  et al.  Mutations in the RPGR gene cause X-linked cone dystrophy. Hum Mol Genet 2002;11 (5) 605- 611
PubMed
Ayyagari  RDemirci  FYLiu  J  et al.  X-linked recessive atrophic macular degeneration from RPGR mutation. Genomics 2002;80 (2) 166- 171
PubMed
Ebenezer  NDMichaelides  MJenkins  SA  et al.  Identification of novel RPGR ORF15 mutations in X-linked progressive cone-rod dystrophy (XLCORD) families. Invest Ophthalmol Vis Sci 2005;46 (6) 1891- 1898
PubMed
Sharon  DSandberg  MARabe  VW  et al.  RP2 and RPGR mutations and clinical correlations in patients with X-linked retinitis pigmentosa. Am J Hum Genet 2003;73 (5) 1131- 1146
PubMed
García-Hoyos  MGarcia-Sandoval  BCantalapiedra  D  et al.  Mutational screening of the RP2 and RPGR genes in Spanish families with X-linked retinitis pigmentosa. Invest Ophthalmol Vis Sci 2006;47 (9) 3777- 3782
PubMed
Meindl  ADry  KHerrmann  K  et al.  A gene (RPGR) with homology to the RCC1 guanine nucleotide exchange factor is mutated in X-linked retinitis pigmentosa (RP3). Nat Genet 1996;13 (1) 35- 42
PubMed
Yokoyama  AMaruiwa  FHayakawa  M  et al.  Three novel mutations of the RPGR gene exon ORF15 in three Japanese families with X-linked retinitis pigmentosa. Am J Med Genet 2001;104 (3) 232- 238
PubMed
Bader  IBrandau  OAchatz  H  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 2003;44 (4) 1458- 1463
PubMed
Jin  ZBLiu  XQUchida  A  et al.  Novel deletion spanning RCC1-like domain of RPGR in Japanese X-linked retinitis pigmentosa family. Mol Vis 2005;11535- 541
PubMed
Wright  AFShu  X Focus on molecules: RPGR. Exp Eye Res 2006;85 (1) 1- 210.1016/j.exer.2006.03.006
Jin  Z-BHayakawa  MMurakami  ANao-i  N Rcc1-like domain and ORF15: essentials in RPGR gene. Hollyfield  JGAnderson  RELaVail  MMedsRetinal Degenerative Diseases. New York, NY Springer2006;
Zhang  QAcland  GMWu  WX  et al.  Different RPGR exon ORF15 mutations in Canids provide insights into photoreceptor cell degeneration. Hum Mol Genet 2002;11 (9) 993- 1003
PubMed
Pelletier  VJambou  MDelphin  N  et al.  Comprehensive survey of mutations in RP2 and RPGR in patients affected with distinct retinal dystrophies: genotype-phenotype correlations and impact on genetic counseling. Hum Mutat 2007;2881- 91
PubMed
Breuer  DKYashar  BMFilippova  E  et al.  A comprehensive mutation analysis of RP2 and RPGR in a North American cohort of families with X-linked retinitis pigmentosa. Am J Hum Genet 2002;70 (6) 1545- 1554
PubMed
Pusch  CMBroghammer  MJurklies  BBesch  DJacobi  FK Ten novel ORF15 mutations confirm mutational hot spot in the RPGR gene in European patients with X-linked retinitis pigmentosa. Hum Mutat 2002;20 (5) 405
PubMed
Rebello  GVorster  AGreenberg  J  et al.  Analysis of RPGR in a South African family with X-linked retinitis pigmentosa: research and diagnostic implications. Clin Genet 2003;64 (2) 137- 141
PubMed
Andréasson  SBreuer  DKEksandh  L  et al.  Clinical studies of X-linked retinitis pigmentosa in three Swedish families with newly identified mutations in the RP2 and RPGR-ORF15 genes. Ophthalmic Genet 2003;24 (4) 215- 223
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Pedigree of the family with X-linked retinitis pigmentosa and segregation analysis of the microsatellite at Xp11.3-11.4. Closed symbols indicate subjects with retinitis pigmentosa; open symbols, unaffected individuals; squares, males; circles, females; dotted circles, female carriers; bars over the symbols, personally examined subjects; and arrow, propositus.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Representative fundus photographs and electroretinography (ERG) results of individuals with X-linked retinitis pigmentosa, including the propositus (III:1) (A), the carrier II:3 (B), the patient I:3 (C), and the carrier III:2 (D).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Sequence chromatograms. The normal alleles (A) were compared with the hemizygous (B) and heterozygous (C) mutations identified in the study. The chromatograms are shown as the reverse sequence. The square indicates the deleted 2 nucleotides.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Summary of Clinical Findings for the Family With X-linked Retinitis Pigmentosa
Table Graphic Jump LocationTable 2. Summary of the Mutations Downstream of Codon 365 in Open Reading Frame 15

References

Bergen  AAVan den Born  LISchuurman  EJ  et al.  Multipoint linkage analysis and homogeneity tests in 15 Dutch X-linked retinitis pigmentosa families. Ophthalmic Genet 1995;16 (2) 63- 70
PubMed
Fujita  RBuraczynska  MGieser  L  et al.  Analysis of the RPGR gene in 11 pedigrees with the retinitis pigmentosa type 3 genotype: paucity of mutations in the coding region but splice defects in two families. Am J Hum Genet 1997;61 (3) 571- 580
PubMed
Musarella  MAAnson-Cartwright  LLeal  SM  et al.  Multipoint linkage analysis and heterogeneity testing in 20 X-linked retinitis pigmentosa families. Genomics 1990;8 (2) 286- 296
PubMed
Teague  PWAldred  MAJay  M  et al.  Heterogeneity analysis in 40 X-linked retinitis pigmentosa families. Am J Hum Genet 1994;55 (1) 105- 111
PubMed
Vervoort  RLennon  ABird  AC  et al.  Mutational hot spot within a new RPGR exon in X-linked retinitis pigmentosa. Nat Genet 2000;25 (4) 462- 466
PubMed
Demirci  FYRigatti  BWWen  G  et al.  X-linked cone-rod dystrophy (locus COD1): identification of mutations in RPGR exon ORF15. Am J Hum Genet 2002;70 (4) 1049- 1053
PubMed
Yang  ZPeachey  NSMoshfeghi  DM  et al.  Mutations in the RPGR gene cause X-linked cone dystrophy. Hum Mol Genet 2002;11 (5) 605- 611
PubMed
Ayyagari  RDemirci  FYLiu  J  et al.  X-linked recessive atrophic macular degeneration from RPGR mutation. Genomics 2002;80 (2) 166- 171
PubMed
Ebenezer  NDMichaelides  MJenkins  SA  et al.  Identification of novel RPGR ORF15 mutations in X-linked progressive cone-rod dystrophy (XLCORD) families. Invest Ophthalmol Vis Sci 2005;46 (6) 1891- 1898
PubMed
Sharon  DSandberg  MARabe  VW  et al.  RP2 and RPGR mutations and clinical correlations in patients with X-linked retinitis pigmentosa. Am J Hum Genet 2003;73 (5) 1131- 1146
PubMed
García-Hoyos  MGarcia-Sandoval  BCantalapiedra  D  et al.  Mutational screening of the RP2 and RPGR genes in Spanish families with X-linked retinitis pigmentosa. Invest Ophthalmol Vis Sci 2006;47 (9) 3777- 3782
PubMed
Meindl  ADry  KHerrmann  K  et al.  A gene (RPGR) with homology to the RCC1 guanine nucleotide exchange factor is mutated in X-linked retinitis pigmentosa (RP3). Nat Genet 1996;13 (1) 35- 42
PubMed
Yokoyama  AMaruiwa  FHayakawa  M  et al.  Three novel mutations of the RPGR gene exon ORF15 in three Japanese families with X-linked retinitis pigmentosa. Am J Med Genet 2001;104 (3) 232- 238
PubMed
Bader  IBrandau  OAchatz  H  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 2003;44 (4) 1458- 1463
PubMed
Jin  ZBLiu  XQUchida  A  et al.  Novel deletion spanning RCC1-like domain of RPGR in Japanese X-linked retinitis pigmentosa family. Mol Vis 2005;11535- 541
PubMed
Wright  AFShu  X Focus on molecules: RPGR. Exp Eye Res 2006;85 (1) 1- 210.1016/j.exer.2006.03.006
Jin  Z-BHayakawa  MMurakami  ANao-i  N Rcc1-like domain and ORF15: essentials in RPGR gene. Hollyfield  JGAnderson  RELaVail  MMedsRetinal Degenerative Diseases. New York, NY Springer2006;
Zhang  QAcland  GMWu  WX  et al.  Different RPGR exon ORF15 mutations in Canids provide insights into photoreceptor cell degeneration. Hum Mol Genet 2002;11 (9) 993- 1003
PubMed
Pelletier  VJambou  MDelphin  N  et al.  Comprehensive survey of mutations in RP2 and RPGR in patients affected with distinct retinal dystrophies: genotype-phenotype correlations and impact on genetic counseling. Hum Mutat 2007;2881- 91
PubMed
Breuer  DKYashar  BMFilippova  E  et al.  A comprehensive mutation analysis of RP2 and RPGR in a North American cohort of families with X-linked retinitis pigmentosa. Am J Hum Genet 2002;70 (6) 1545- 1554
PubMed
Pusch  CMBroghammer  MJurklies  BBesch  DJacobi  FK Ten novel ORF15 mutations confirm mutational hot spot in the RPGR gene in European patients with X-linked retinitis pigmentosa. Hum Mutat 2002;20 (5) 405
PubMed
Rebello  GVorster  AGreenberg  J  et al.  Analysis of RPGR in a South African family with X-linked retinitis pigmentosa: research and diagnostic implications. Clin Genet 2003;64 (2) 137- 141
PubMed
Andréasson  SBreuer  DKEksandh  L  et al.  Clinical studies of X-linked retinitis pigmentosa in three Swedish families with newly identified mutations in the RP2 and RPGR-ORF15 genes. Ophthalmic Genet 2003;24 (4) 215- 223
PubMed

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