HGNC Approved Gene Symbol: RPGR
Cytogenetic location: Xp11.4 Genomic coordinates (GRCh38): X:38,269,163-38,327,509 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.4 | Cone-rod dystrophy, X-linked, 1 | 304020 | X-linked recessive | 3 |
| Macular degeneration, X-linked atrophic | 300834 | X-linked recessive | 3 | |
| Retinitis pigmentosa 3 | 300029 | X-linked | 3 | |
| Retinitis pigmentosa, X-linked, and sinorespiratory infections, with or without deafness | 300455 | X-linked | 3 |
Meindl et al. (1996) isolated and sequenced cosmids from the region of the microdeletions in patients with retinitis pigmentosa-3 (300029) and used these cosmids to make exon predictions. They thus identified a gene, provisionally named RPGR (retinitis pigmentosa GTPase regulator), which gives rise to a ubiquitously expressed 29-kb transcript. The predicted 90-kD RPGR protein contains in its N-terminal half a tandem repeat structure highly similar to the regulator of chromosome condensation (RCC1; 179710), which regulates the GTPase RAN (601179). Meindl et al. (1996) identified 8 potential asparagine-linked glycosylation sites along the N-terminal two-thirds of the predicted RPGR protein. The C terminus of the protein contains a cluster of basic residues followed by a consensus isoprenylation site. The authors noted that confirmation of the isoprenylation of this site would establish a novel means of membrane anchorage for a GTPase regulator.
Roepman et al. (1996) used a cosmid spanning a microdeletion in an RP3 patient to screen cDNA libraries. They then isolated additional cosmids that flanked the microdeletion region. Shotgun cosmid sequencing enabled them to sequence 32,895 bp of DNA. Computer-assisted analysis of this sequence predicted numerous additional exons which were confirmed by cDNA cloning. Sequence comparisons revealed that the deduced product of the RPGR gene showed strong similarity with RCC1.
Kirschner et al. (1999) studied the expression of the RPGR gene by Northern blot hybridization, cDNA library screening, and RT-PCR in various organs of mouse and human and identified at least 12 alternatively spliced isoforms. Some of the transcripts are tissue-specific and contain novel exons, which elongate or truncate the previously reported open reading frame of the mouse and human RPGR gene. Kirschner et al. (1999) identified a new exon, designated exon 15A by them, which is expressed exclusively in human retina and mouse eye and contains a premature stop codon. The deduced polypeptide lacked 169 amino acids from the C terminus of the ubiquitously expressed variant, including an isoprenylation site.
Kirschner et al. (2001) compared the genomic sequence of the human and mouse RPGR genes. Each spans a region of nearly 59 kb, and all previously identified exons are conserved between the 2 species. A sequence comparison identified 28 conserved sequence elements in introns, upstream of exon 1, within the promoter region, and downstream of the most 3-prime exon. Some of the intronic conserved sequence elements flank tissue-specific exons and therefore may represent important regulatory elements for alternative splicing. Comparative Northern blot hybridization of ubiquitous and tissue-specific RPGR probes identified high molecular mass transcripts with similar expression patterns in both human and mouse. These transcripts range from 6 to 15 kb and suggest the presence of additional transcribed sequences within RPGR.
Vervoort et al. (2000) sequenced a 172-kb region containing the entire RPGR gene. Analysis of the sequence disclosed a novel 3-prime terminal exon that was mutated in 60% of XLRP patients examined. This exon encodes 567 amino acids, with a repetitive domain rich in glutamic acid residues. The sequence is conserved in the mouse, bovine, and Fugu rubripes genes. It is preferentially expressed in mouse and bovine retina, further supporting its importance for retinal function. In addition to the 19 exons previously reported, Vervoort et al. (2000) found 5 additional exons: 15b1, 15b2, 15a, ORF14, and ORF15. Exons 15b1 and 15b2 are 2 overlapping exons within intron 15 that use alternative acceptor splice sites and the same donor site. Their inclusion is predicted to result in premature termination of translation. Exon 15a, which is a third internal exon within intron 15 and also encodes a premature stop codon, is identical with exon 15a reported previously (Kirschner et al., 1999). Exon ORF14 corresponds to the mouse exon 14-14a-15 (Kirschner et al., 1999); its inclusion does not disrupt the reading frame. Exon ORF15 is a large 3-prime terminal exon consisting of exon 15 and extending into part of intron 15. The predicted exon ORF15 protein domain contains an unusual region of low sequence complexity with high glutamic acid and glycine content (Plaid domain).
By RT-PCR analysis of human retina cDNA, Neidhardt et al. (2007) identified a novel exon in intron 9, designated exon 9A, of the RPGR gene. The novel exon starts 418 bp downstream of the splice donor site of exon 9 and contains 136 nucleotides. Exon 9A is present in a novel RPGR splice variant that truncates the RCC1 homologous protein domain of RPGR by 48 amino acids, yielding a 353-residue protein with a molecular mass of about 45 kD. There was strong expression of the 9A variant predominantly in the inner segment of human cones with a weaker signal in rods. Immunoprecipitation studies showed that the 9A variant binds distinct RPGRIP1 (605446) variants, suggesting functional relevance. The expression of mRNA containing exon 9A was quantified to approximately 4% of RPGR in normal individuals.
Ghosh et al. (2010) noted that there are 2 major isoforms of RPGR detected in the retina: RPGR(1-19), which has 19 exons and 815 amino acids, and RPGR(1-ORF15), which has 15 exons plus part of intron 15 and 1,152 amino acids. Both isoforms share exons 1 through 15 and N-terminal RCC1-like domain (RLD), whereas RPGR(1-ORF15) has a glu-gly-rich C-terminal domain.
Using immunogold electron microscopy with mouse and human retina, Khanna et al. (2005) found that, in addition to axoneme, RPGR-ORF15 localized to basal bodies of photoreceptor connecting cilium. It also colocalized with acetylated alpha-tubulin (see 602529) at the tip and tail axoneme of mouse sperm flagella and at primary cilia of MDCK canine kidney cells.
Boylan and Wright (2000) and Roepman et al. (2000) identified the RPGRIP1 gene (605446) and found that it encodes several alternatively spliced gene products that interact specifically with RPGR. Roepman et al. (2000) determined that RPGR and RPGRIP1 colocalized in the outer segment of rod photoreceptors, which is in agreement with the retinitis pigmentosa phenotype observed in RP3 patients.
Mavlyutov et al. (2002) used isoform-specific antibodies to demonstrate that RPGR and RPGRIP isoforms are distributed and colocalized at restricted foci throughout the outer segments of human and bovine (but not murine) rod photoreceptors. In humans, these proteins are also localized in cone outer segments, and RPGRIP is expressed in other neurons such as amacrine cells. The authors proposed the existence of species-specific subcellular processes governing the function and/or organization of the photoreceptor outer segment as reflected by the species-specific localization of RPGR and RPGRIP protein isoforms in this compartment. They contended that this may provide a rationale for the disparity of phenotypes among species and among various human mutations.
Using immunofluorescence and serial retinal sectioning, Hong et al. (2003) established the subcellular localization of RPGR in mice and other mammalian species; they found RPGR in connecting cilia of rods and cones and in a homologous structure, the transitional zone of motile cilia in airway epithelia. There was no evidence for species-specific variation of RPGR localization.
By immunohistochemistry, Iannaccone et al. (2003) found that the RPGR gene was expressed throughout the outer segments of human rod and cone photoreceptors, within the epithelial lining of human bronchial and sinus tissues, and in human fetal cochlea, including the stria vascularis, the suprastrial cells, and the apical portion of the spiral limbus. The findings broadened the possible functional roles of RPGR and provided evidence for a broad phenotype in patients with RPGR mutations.
Hong et al. (2004) created an RPGR transgene transcript using alternative splicing involving the purine-rich region of the ORF15 exon, generating a shortened mRNA and a premature stop codon. This truncation mutant caused more rapid photoreceptor degeneration than that in the RPGR null mutant. The disease course was similar, whether the transgene was coexpressed with wildtype RPGR or expressed alone on the RPGR null background. The authors concluded that certain truncated forms of RPGR can behave as a dominant, gain-of-function mutant. These data suggested that human RPGR mutations were not necessarily null and some might also act as dominant alleles, leading to a more severe phenotype than a null mutant.
RPGR, which is essential for the maintenance of photoreceptor viability, is expressed as constitutive and ORF15 variants because of alternative splicing. Hong et al. (2005) examined whether the retina-specific ORF15 variant alone could substantially substitute for RPGR function and tested whether the highly repetitive purine-rich region of ORF15 could be abbreviated without ablating the function, so as to accommodate RPGR replacement genes in adeno-associated virus (AAV) vectors. A cDNA representing mouse Rpgr-ORF15 but shortened by 654 bp in the repetitive region was placed under the control of a chicken beta-actin (CBA) hybrid promoter and used to create transgenic chimeras that were crossed with Rpgr knockout mice. In mice expressing the transgene but null for endogenous Rpgr, transgenic Rpgr-ORF15 was found in the connecting cilia of rod and cone photoreceptors at approximately 20% of the wildtype level. Photoreceptor morphology, cone opsin localization, expression of GFAP (137780) (a marker of retinal degeneration), and ERGs were consistent with the transgene exerting substantial rescue of retinal degeneration due to loss of endogenous Rpgr. Hong et al. (2005) concluded that RPGR-ORF15 is the functionally significant variant in photoreceptors and that the length of its repetitive region can be reduced while preserving its function.
In cultured mammalian cells, Shu et al. (2005) showed that both RPGR-ORF15 and RPGRIP1 (605446) localized to centrioles. By multiple methods, the authors showed that the C2 domain of RPGR-ORF15 interacted with the shuttling protein nucleophosmin (NPM1; 164040), which is a protein chaperone that shuttles between the nucleoli and the cytoplasm and has been associated with licensing of centrosomal division.
By immunoprecipitation of bovine retinal axoneme-enriched fraction, followed by mass spectrometric analysis of proteins separated by SDS-PAGE, Khanna et al. (2005) found that Rpgr-Orf15 bound the ATP-binding proteins Smc1 (SMC1A; 300040) and Smc3 (606062). Protein pull-down experiments revealed that the N-terminal RLD domain of human RPGR-ORF15 bound endogenous bovine Smc1 and Smc3. Bovine Rpgr-Orf15 also associated with Ift88 (600595) and the microtubule motor proteins Kif3a (604683) and Kap3 (KIFAP3; 601836) in an axoneme multiprotein complex. Khanna et al. (2005) concluded that RPGR-ORF15 may be involved in microtubule organization or regulation of transport in primary cilia.
By coimmunoprecipitation of bovine retinal extract, Murga-Zamalloa et al. (2010) found that Rpgr interacted with the small GTPase Rab8a (165040), which has a role in cilia biogenesis and maintenance. Human RPGR interacted predominantly with the GDP-bound form of human RAB8A and stimulated GDP/GTP exchange. Disease-causing mutations in RPGR diminished its interaction with RAB8A and/or reduced its GDP/GTP exchange activity. Depletion of RPGR in human retinal pigment epithelial cells disrupted association of RAB8A with cilia and resulted in shortened primary cilia.
Shu et al. (2007) stated that a total of 240 different mutations in the RPGR gene had been reported, including 24 novel mutations identified by the authors. Of the 240 mutations, 95% are associated with XLRP, 3% with cone, cone-rod dystrophy or atrophic macular atrophy, and 2% with syndromal retinal dystrophies with ciliary dyskinesia and hearing loss.
Branham et al. (2012) screened 214 male patients with simplex retinal degenerative disease, 185 with RP and 29 with cone/cone-rod dystrophy (COD/CORD), for mutations in the RPGR and RP2 (300757) genes. They identified pathogenic mutations in 32 (15%) of the patients. Four patients with COD/CORD had a mutation in the ORF15 mutation hotspot of the RPGR gene. Of the RP patients, 3 had mutations in RP2 and 25 had mutations in RPGR (including 23 in the ORF15 region). Branham et al. (2012) concluded that their results demonstrated a substantial contribution of RPGR mutations to retinal degenerations, and in particular to simplex RP. They suggested that RPGR should be considered as a first tier gene for screening isolated males with retinal degeneration.
Retinitis Pigmentosa 3
Meindl et al. (1996) provided evidence that loss-of-function mutations within RPGR are responsible for X-linked retinitis pigmentosa-3 by identifying 2 small intragenic deletions and 2 nonsense and 3 missense mutations in highly conserved residues in unrelated patients with X-linked RP.
Roepman et al. (1996) screened the Xp21.1-p11.4 RP3 locus interval for microdeletions using a novel technique they called YAC representation hybridization (YRH). Application of this technique led to the generation of a defined amplifiable subset of restriction fragments representing the insert of a YAC spanning the region of interest. The mixture of PCR products was used to study Southern blots of restriction-digested genomic DNA. In 1 of 30 patients with X-linked retinitis pigmentosa, they detected a 6.4-kb microdeletion.
Roepman et al. (1996) detected mutations in the RPGR gene in RP patients and not in controls. Mutation screening was carried out in 28 patients by means of SSCP analysis. They designed intron primers for PCR amplification of 10 exons and detected 5 bandshifts in patients. The corresponding PCR fragments were sequenced and 3 different nucleotide exchanges (312610.0001, 312610.0002, and 312610.0003), and one 4-bp deletion (312610.0004) were identified. None of these changes were detected in 84 male controls. The 6 most 3-prime exons showed no mutations but did reveal several polymorphisms. The 3-prime end of the gene is, however, disrupted by the 6.4-kb deletion which is present in a patient with X-linked retinitis pigmentosa. Roepman et al. (1996) noted that the 5-prime end of the gene and the promoter region had not yet been cloned.
To characterize RPGR mutations in a systematic way, Fujita et al. (1997) identified 11 RP3 families by haplotype analysis. Sequence analysis of the PCR-amplified genomic DNA from patients representing these RP3 families showed no causative mutation in RPGR exons 2 to 19, spanning more than 98% of the coding region. In patients from 2 families, however, they identified transition mutations in the intron region near splice sites (IVS10+3; 312610.0005 and IVS13-8). RNA analysis showed that both splice site mutations resulted in the generation of aberrant RPGR transcripts. The results supported the hypothesis that mutations in the RPGR gene are not a common defect in the RP3 subtype of X-linked RP and that the majority of causative mutations may reside either in as yet unidentified RPGR exons or in another nearby gene at Xp21.1.
Buraczynska et al. (1997) examined the RPGR gene in a cohort of 80 affected males from apparently unrelated X-linked RP families by direct sequencing of the PCR-amplified products from genomic DNA. Fifteen different putative disease-causing mutations were identified in 17 of the 80 families: 4 nonsense mutations, 1 missense mutation, 6 microdeletions, and 4 intronic-sequence substitutions resulting in splice defects. In their Figure 2, they mapped the location of 12 mutations reported by Meindl et al. (1996) and Roepman et al. (1996) and the 15 different mutations identified in this study. Most of the mutations were detected in the conserved N-terminal region of the RPGR protein, containing tandem repeats homologous to those present in the RCC1 protein. In agreement with previous studies, they were able to demonstrate RPGR mutations in only about 20% of the examined X-linked RP patients. On the other hand, the RP3 subtype consistently accounts for 60 to 90% of families localized by linkage and haplotype genotyping. Buraczynska et al. (1997) raised the possibility that the RPGR gene contains unidentified mutation hotspots in sequences that have not been screened, such as the promoter region or intronic sequences and exon 1. The authors could not rule out the alternative possibility of another gene located in proximity to RPGR at Xp21.1 that also causes RP when mutated.
Souied et al. (1997) described 9 families that showed an X-linked pattern of inheritance with a total of 28 affected males and 34 affected females. The females in these families met criteria for the diagnosis of retinitis pigmentosa. The males had a delayed onset of disease, in the second decade, with central vision being preserved until 40 to 45 years of age. Linkage to the RP3 locus was demonstrated, but SSCP and sequence analysis of the RPGR gene demonstrated no mutations. Souied et al. (1997) suggested that these families demonstrated an X-linked dominant form of RP and that the negative mutation results may be explained either by allelic heterogeneity at the RP3 locus or involvement of a distinct locus mapping close to RP3.
Kirschner et al. (1999) demonstrated that the novel RPGR exon 15A that they identified was deleted in a family with X-linked RP (312610.0008). Kirschner et al. (1999) concluded that their results indicate tissue-dependent regulation of alternative splicing of the RPGR gene and that the presence of the retina-specific transcript may explain why phenotypic aberrations in RP3 are confined to the eye.
Miano et al. (1999) found a total of 29 different RPGR mutations identified in northern European and United States patients. They performed mutation analysis of the RPGR gene in a cohort of 49 southern European males with XLRP. By multiplex SSCA and direct sequencing of all 19 RPGR exons, 7 different mutations, all novel, were identified in 8 of the 49 families; these included 3 splice site mutations, 2 microdeletions, and 2 missense mutations. RNA analysis showed that the 3 splice site defects resulted in the generation of aberrant RPGR transcripts. Six of these mutations were detected in the conserved N-terminal region of RPGR protein, containing tandem repeats homologous to repeats within the RCC1 protein (179710). Strikingly, none of the RPGR mutations reported in other populations were identified in this series.
Because mutations in the RPGR gene were found in fewer than the 70 to 75% of XLRP patients predicted from linkage studies, Vervoort et al. (2000) hypothesized that mutations in the remaining XLRP patients may have resided in undiscovered exons of RPGR and sequenced a 172-kb region containing the entire gene. Analysis of the sequence disclosed a new 3-prime terminal exon, ORF15, that was mutated in 60% of XLRP patients examined. Vervoort et al. (2000) concluded that mutations in RPGR are the only cause of RP3 type XLRP and account for the disease in over 70% of XLRP patients and an estimated 11% of all RP patients. Vervoort et al. (2000) found 28 XLRP patients with mutations in exon ORF15, each of which leads to premature termination of translation. Most were small nucleotide deletions, and 5 of them were substitutions leading to nonsense mutation. None of the mutations were detected in 150 control chromosomes. The high frequency of mutations within the terminal exon ORF15 (17 different mutations in 1 kb) compared with other parts of the same RPGR transcript (6 mutations in 1.6 kb), suggested that it is a mutation hotspot. Vervoort et al. (2000) found each of 5 different mutations on at least 2 different haplotypes, indicating recurrent mutation.
In each of 3 unrelated Japanese families segregating X-linked retinitis pigmentosa, Yokoyama et al. (2001) identified a novel mutation in exon ORF15. The mutations were of insertion/deletion type and were predicted to lead to a frameshift, resulting in a truncated protein. The findings supported the previous hypothesis that exon ORF15 is a mutation hotspot. Affected males had typical retinitis pigmentosa, whereas the obligate carrier females showed a wide clinical spectrum, ranging from minor symptoms to severe visual disability. Some carrier females showed typical RP, and most carriers manifested high myopia and astigmatism, with insufficiently corrected visual acuity.
In 4 of the 9 families with XLRP reported by Souied et al. (1997), Rozet et al. (2002) identified mutations in exon ORF15 of the RPGR gene. Rozet et al. (2002) also reported 5 additional affected families with mutations in ORF15. All 7 of the identified mutations were predicted to result in a truncated protein. Rozet et al. (2002) noted that the age at onset in affected females was delayed compared to affected males (20 to 40 years vs 10 to 20 years, respectively).
Vervoort and Wright (2002) reviewed mutations in RPGR in X-linked retinitis pigmentosa (RP3). They commented on the fact that exon ORF15 is a hotspot for mutation, at least in the British population, in which it harbors 80% of the mutations found within a sample of 47 X-linked retinitis pigmentosa patients.
In a North American cohort of 234 families with RP, Breuer et al. (2002) conducted a comprehensive screen of the RP2 (300757) and RPGR (including ORF15) genes and their 5-prime upstream regions. Of these families, 91 (39%) showed definitive X-linked inheritance, an additional 88 (38%) revealed a pattern consistent with X-linked disease, and the remaining 55 (23%) were simplex male patients with RP who had an early onset and/or severe disease. In agreement with previous studies, they showed that mutations in the RP2 gene and in the original 19 RPGR exons are detected in less than 10% and approximately 20% of XLRP probands, respectively. Their studies revealed RPGR ORF15 mutations in an additional 30% of 91 well-documented families with X-linked recessive inheritance and in 22% of the total 234 probands analyzed. They suggested that mutations in an uncharacterized RPGR exon(s), intronic changes, or another gene in the region may be responsible for the disease in the remainder of this North American cohort.
Bader et al. (2003) screened 58 German XLRP families and found RP2 mutations in 8% and RPGR mutations in 71%. They also reported a detailed strategy for analyzing the RPGR ORF15 mutation hot spot, which could not be screened by standard procedures.
Sharon et al. (2003) determined the mutation spectrum of the RP2 and RPGR genes in patients with X-linked retinitis pigmentosa. They screened 187 unrelated male patients and found 10 mutations in RP2, 2 of which were novel, and 80 mutations in RPGR, 41 of which were novel. Patients with RP2 mutations had, on average, lower visual acuity but similar visual field area, final dark-adapted threshold, and 30-Hz ERG amplitude compared with those with RPGR mutations. Among the 66% of patients with RPGR mutations in ORF, regression analysis showed that the final dark-adapted threshold became lower (i.e., closer to normal) and that the 30-Hz ERG amplitude increased as the length of the wildtype ORF15 amino acid sequence increased. Furthermore, as the length of the abnormal amino acid sequence following ORF15 frameshift mutations increased, the severity of disease increased. In summary, these cross-sectional analyses suggested that, at a given age, patients with RP2 mutations retained less visual acuity than do patients with RPGR mutations and that, among patients with RPGR mutations, those with ORF15 mutations have milder disease than do patients with mutations in exons 1 to 14.
Demirci et al. (2006) reported a 16-year-old boy with RP (300029) and bilateral Coats-like vasculopathy (see 300216) in whom they identified a novel nonsense mutation in ORF15 of the RPGR gene (312610.0024).
Pelletier et al. (2007) reported the screening of the RP2 and RPGR genes in a cohort of 127 French families comprising 93 familial cases of retinitis pigmentosa suggesting X-linked inheritance, including 48 of 93 families; 7 male sibships of RP; 25 sporadic male cases of RP; and 2 cone dystrophies (COD). They identified a total of 14 RP2 mutations, 12 of which were novel, in 14 of 88 familial cases of RP and 1 of 25 sporadic male cases (4%). In 13 of 14 of the familial cases, no expression of the disease was noted in females, while in 1 of 14 families 1 woman developed retinitis pigmentosa in the third decade. A total of 42 RPGR mutations, 26 of which were novel, were identified in 80 families, including 69 of 88 familial cases (78.4%); 2 of 7 male sibship cases (28.6%); 8 of 25 sporadic male cases (32%); and 1 of 2 COD. No expression of the disease was noted in females in 41 of 69 familial cases (59.4%), while at least 1 severely affected woman was recognized in 28 of 69 families (40.6%). The frequency of RP2 and RPGR mutations in familial cases of retinitis pigmentosa suggestive of X-linked transmission was in accordance with that reported elsewhere (RP2: 15.9% vs 6-20%; RPGR: 78.4% vs 55-90%). About 30% of male sporadic cases and 30% of male sibships of RP carried RP2 or RPGR mutations, confirming the pertinence of the genetic screening of XLRP genes in male patients affected with RP commencing in the first decade and leading to profound visual impairment before the age of 30 years.
Sandberg et al. (2007) measured the rates of visual acuity, visual field, and electroretinogram (ERG) loss in 2 large cohorts, one of patients with XLRP due to mutations in the RPGR gene and the other of patients with autosomal dominant RP due to mutations in the RHO gene (see 180380). Patients with RPGR mutations lost Snellen visual acuity at more than twice the mean rate of patients with RHO mutations. The median age of legal blindness was 32 years younger in patients with RPGR mutation than in patients with RHO mutations. Legal blindness was due primarily to loss of visual acuity in RPGR patients and to loss of visual field in RHO patients. Loss of acuity in RPGR patients appeared to be associated with foveal thinning.
In affected individuals from an Israeli family with 'semi-dominant' X-linked retinitis pigmentosa, in which obligatory female carriers manifested high myopia, low visual acuity, constricted visual fields, and severely reduced electroretinogram amplitudes, Banin et al. (2007) identified the G275S mutation in the RPGR gene (312610.0003). The authors stated that obligate carriers from 2 unrelated Danish families in which Roepman et al. (1996) previously identified this mutation had no visual complaints and normal to slightly reduced retinal function. The disease-related RPGR haplotype of the Israeli family was found to be different from that of 2 Danish families, indicating that the G275S mutation arose twice independently on different X-chromosome backgrounds. Genetic analysis excluded skewed X-inactivation patterns, chromosomal abnormalities, distorted RPGR expression levels, and mutations in 3 candidate genes as the cause for the differences in disease severity of female carriers. Banin et al. (2007) suggested that an additional gene or genes linked to RPGR modulate disease expression in severely affected carriers.
Nishiguchi et al. (2013) identified a Japanese male RP patient who was heterozygous for a frameshift mutation in the ciliary gene NEK2 (604043.0001), but who also carried a frameshift mutation in RPGR (312610.0026). Studies in zebrafish suggested that the RPGR allele interacts in trans with the NEK2 locus to exacerbate photoreceptor defects.
Among female carriers from 45 families with RP3, Comander et al. (2015) found that those with RPGR ORF15 mutations tended to have worse visual function than those with RPGR exon 1 through 14 mutations.
Cone-Rod Degeneration
Mears et al. (2000) restudied a family with what was labeled 'X-linked dominant cone-rod degeneration' (300029) and thought to map to Xp22.13-p22.11, and remapped the disorder to Xp22.1-p11.4. This new interval overlapped the RP3 (RPGR) and the CORDX1 (304020) genes. They identified a de novo insertion (312610.0013) in exon ORF15 of the RPGR gene. The identification of an RPGR mutation in a family with a severe form of cone-rod degeneration suggested that RPGR mutations may encompass a broader phenotypic spectrum than had previously been recognized in 'typical' retinitis pigmentosa.
Retinitis Pigmentosa and Sinopulmonary Infections with or without Deafness
In the family with X-linked retinitis pigmentosa with recurrent respiratory infections (300455) described by van Dorp et al. (1992), Dry et al. (1999) identified an IVS5+1G-T splice site mutation in the RPGR gene (312610.0016).
In a family in which affected males in an X-linked recessive pedigree pattern had retinitis pigmentosa associated with impaired hearing and sinorespiratory infections, Zito et al. (2003) identified A 2-bp deletion, 845delTG, in exon 8 of the RPGR gene (312610.0019).
In a family in which a mother had retinitis pigmentosa and her 2 sons had retinitis pigmentosa, multiple respiratory infections, and primary ciliary dyskinesia, Moore et al. (2006) identified a 57-bp deletion in the RPGR gene (312610.0023).
Atrophic Macular Degeneration
Ayyagari et al. (2002) described a family in which 10 males had primarily macular atrophy causing progressive loss of visual acuity with minimal peripheral visual impairment (300834). One additional male showed extensive macular degeneration plus peripheral loss of retinal pigment epithelium and choriocapillaries. Full-field electroretinograms showed normal cone and rod responses in some affected males despite advanced macular degeneration. In affected members of this family, Ayyagari et al. (2002) identified a G-to-T transversion at nucleotide 1164 of intron 15 (312610.0017) that cosegregated with the disease and may create a donor splice site. Thus the phenotypic range associated with this gene was expanded.
Hong et al. (2000) created an RPGR-deficient murine model of RP3 by gene knockout. In the mutant mice, cone photoreceptors exhibited ectopic localization of cone opsins in the cell body and synapses, and rod photoreceptors had a reduced level of rhodopsin. Subsequently, both rod and cone photoreceptors degenerated. RPGR was found normally localized to the connecting cilia of rod and cone photoreceptors. The data pointed to a role for RPGR in maintaining the polarized protein distribution across the connecting cilium by facilitating directional transport or restricting redistribution. The function of RPGR is essential for the long-term maintenance of photoreceptor viability.
X-linked progressive retinal atrophy (XLPRA) in the Siberian Husky dog closely resembles XLRP in humans. Zeiss et al. (2000) established a linkage map of the canine X chromosome, and determined that XLPRA was tightly linked to an intragenic RPGR polymorphism (lod = 11.7, zero recombination), thus confirming locus homology with RP3. They cloned the full-length canine RPGR cDNA and 3 additional splice variants. No disease-causing mutation was found in the RPGR-coding sequence of the 4 splice variants characterized, a finding similar to approximately 80% of human XLRP patients whose disease maps to the RP3 locus.
Zhang et al. (2002) found different mutations in exon ORF15 of the RPGR gene in 2 distinct mutant dog strains: XLPRA1 and XLPRA2. Microdeletions resulting in a premature stop or a frameshift mutation produced very different retinal phenotypes, which were allele-specific and consistent for each mutation. The phenotype associated with a frameshift mutation in XLPRA2 was very severe and manifested during retinal development; the phenotype resulting from a nonsense mutation in XLPRA1 was expressed only after normal photoreceptor morphogenesis. The frameshift mutation dramatically alters the deduced amino acid sequence, and the protein aggregates in the endoplasmic reticulum of transfected COS-7 cells.
Beltran et al. (2006) described the course of retinal disease in canine XLPRA2 caused by a 2-nucleotide microdeletion in RPGR ORF15. The disorder is characterized by abnormal photoreceptor maturation followed by progressive rod-cone degeneration and early inner retina remodeling. Abnormal development of photoreceptors was recognizable as early as 3.9 weeks of age. Outer segment (OS) misalignment was followed by their disorganization and fragmentation. Reduction in length and broadening of rod and cone inner segments (IS) was observed next, followed by the focal loss of rod and cone IS later. The proportion of dying photoreceptors peaked at approximately 6 to 7 weeks of age and was significantly reduced after 12 weeks. In addition to rod and cone opsin mislocalization, there was early rod neurite sprouting, retraction of rod bipolar cell dendrites, and increased Mueller cell reactivity. Later in the course of the disease, changes were also noted in horizontal cells and amacrine cells.
Beltran et al. (2007) noted that ciliary neurotrophic factor (CNTF; 118945) had been found to rescue photoreceptors in several animal models. They evaluated treatment with CNTF in XLPRA2 dogs. All CNTF-treated eyes showed early clinical signs of corneal epitheliopathy, subcapsular cataracts, and uveitis. No statistically significant difference in outer nuclear layer thickness was seen between CNTF-treated and control eyes. Prominent retinal remodeling that consisted of an abnormal increase in the number of rods, and in misplacement of some rods, cones, and bipolar and Muller cells, was observed in the peripheral retina of CNTF-treated eyes. In XLPRA2 dogs, intravitreal injection of CNTF failed to prevent photoreceptors from undergoing cell death in the central and midperipheral retina. CNTF also caused ocular side effects and morphologic alterations in the periphery that were consistent with cell dedifferentiation and proliferation. Beltran et al. (2007) concluded that some inherited forms of retinal degeneration may not respond to the neuroprotective effects of CNTF.
Ghosh et al. (2010) showed that rpgr was expressed predominantly in the retina, brain, and gut of zebrafish. In zebrafish retina, rpgr primarily localized to the sensory cilium of photoreceptors. Antisense morpholino-mediated knockdown of rpgr function in zebrafish resulted in reduced length of Kupffer vesicle cilia and was associated with ciliary anomalies including shortened body axis, kinked tail, hydrocephaly, and edema, but did not affect retinal development. These phenotypes could be rescued by wildtype human RPGR. Several RPGR mutants (see, e.g., 312610.0006 and 312610.0020) could also reverse the morpholino-induced phenotype, suggesting their potential hypomorphic function. Selected RPGR mutations observed in XLRP (see, e.g. 312610.0009; E589X) or syndromic retinitis pigmentosa (312610.0016; 312610.0019; 312610.0023) did not completely rescue the rpgr-morpholino phenotype, indicating a more deleterious effect of the mutation on the function of RPGR. Ghosh et al. (2010) proposed that RPGR may be involved in cilia-dependent cascades during development in zebrafish.
Shu et al. (2010) identified 2 genes resembling human RPGR in zebrafish (Zfrpgr1 and Zfrpgr2), both of which are expressed within the nascent and adult eye as well as more widely during development. Zfrpgr2 appears to be functionally orthologous to human RPGR, because it encodes similar protein isoforms (Zfrpgr2(Orf15) and Zfrpgr2(ex1-17)) and, similar to other ciliary proteins, translation suppression causes developmental defects affecting gastrulation and tail and head development. These defects are consistent with a ciliary function and were rescued by human RPGR but not by RPGR mutants causing retinal dystrophy. Unlike in mammals, RPGR knockdown in zebrafish resulted in both abnormal development and increased cell death in the dysplastic retina. Developmental abnormalities in the eye included lamination defects, failure to develop photoreceptor outer segments, and a small eye phenotype, associated with increased cell death throughout the retina. These defects could be rescued by expression of wildtype but not mutant forms of human RPGR. Zfrpgr2 knockdown also resulted in an intracellular transport defect affecting retrograde but not anterograde transport of organelles. Shu et al. (2010) concluded that Zfrpgr2 is necessary both for the normal differentiation and lamination of the retina and to prevent apoptotic retinal cell death, which may relate to its proposed role in dynein-based retrograde transport processes.
In a patient with retinitis pigmentosa-3 (300029), Roepman et al. (1996) identified a T-to-G transversion at nucleotide 420 of their RP3 cDNA sequence, resulting in a phe130-to-cys substitution (F130C). The authors did not denote the amino acid residue position in their publication.
Murga-Zamalloa et al. (2010) showed that the F130C mutation in RPGR did not alter interaction of RPGR with the small GTPase RAB8A (165040) in vitro, but it reduced the ability of RPGR to induce GDP/GTP exchange on RAB8A.
In a patient with retinitis pigmentosa-3 (300029), Roepman et al. (1996) identified a C-to-T transition at nucleotide 734 of their RP3 cDNA sequence, resulting in a pro235-to-ser substitution (P235S). The authors did not denote the amino acid residue position in their publication.
In 2 patients with retinitis pigmentosa-3 (300029), Roepman et al. (1996) identified a G-to-A transition at nucleotide 854 of their RP3 cDNA sequence, resulting in a gly275-to-ser substitution (G275S). The authors did not denote the amino acid residue position in their publication.
In affected individuals from an Israeli family with 'semi-dominant' X-linked retinitis pigmentosa, in which obligatory female carriers manifested high myopia, low visual acuity, constricted visual fields, and severely reduced electroretinogram amplitudes, Banin et al. (2007) identified the G275S mutation in the RPGR gene. The disease-related RPGR haplotype of the Israeli family was found to be different from that of the 2 families previously studied by Roepman et al. (1996) in which obligate carriers of G275S had no visual complaints, indicating that the G275S mutation arose twice independently on different X-chromosome backgrounds. Genetic analysis excluded skewed X-inactivation patterns, chromosomal abnormalities, distorted RPGR expression levels, and mutations in 3 candidate genes as the cause for the differences in disease severity of female carriers. Banin et al. (2007) suggested that an additional gene or genes linked to RPGR modulate disease expression in severely affected carriers.
Roepman et al. (1996) found a 4-bp deletion of nucleotides 1433-1436 of their RP3 cDNA sequence in a patient with retinitis pigmentosa-3 (300029) that resulted in a truncated RP3 protein with 6 abnormal C-terminal amino acids.
In a patient with retinitis pigmentosa-3 (300029), Fujita et al. (1997) found an A-to-G transition in the RPGR gene at the third basepair downstream of exon 10 nucleotide 1304 (sequence designation is according to Meindl et al., 1996) in the splice-donor region of intron 10. The mutation resulted in incorrect splicing of the exon 10-11 junction.
One of the 15 novel mutations identified by Buraczynska et al. (1997) was a G-to-T transversion at nucleotide 238 in exon 3, predicted to lead to a gly60-to-val (G60V) amino acid substitution. Fishman et al. (1998) reported in detail on 2 families with retinitis pigmentosa-3 (300029) with the G60V mutation, one of which was the family earlier reported by Buraczynska et al. (1997). The mutation was associated with a severe clinical phenotype in male patients and a patchy retinopathy without a tapetal-like reflex in carrier females. Psychophysical and electrophysiologic testing on carriers indicated that cone and rod functions were impaired equivalently. When present in carriers, visual field restriction was most apparent in, or limited to, the superotemporal quadrant, which corresponded to the retinal pigmentary changes that tended to occur in the inferonasal retina.
In a black family with retinitis pigmentosa-3 (300029), Fishman et al. (1998) identified a 2-basepair deletion in the RP3 gene. The deletion occurred in exon 13 and created a frameshift and premature stop codon, resulting in a protein truncation. The deletion involved nucleotides 1571 and 1572, a CA dinucleotide. The clinical findings were those characteristic of X-linked retinitis pigmentosa. In 2 obligate carriers, a tapetal-like reflex was not clinically apparent.
In a family with retinitis pigmentosa-3 (300029), Kirschner et al. (1999) identified deletion of exon 15A of the RPGR gene. The splice variant containing exon 15A is expressed only in the retina. The phenotype was of retinal dystrophy with relatively late onset of night blindness, around the age of 10 years. From 30 years of age, very rapid deterioration took place and led to blindness by the age of 37 years. Electrophysiologically, the retinopathy appeared as a cone-rod dystrophy.
One of the unique mutations found by Miano et al. (1999) in south European patients with retinitis pigmentosa-3 (300029) was a C-to-A transversion of nucleotide 355 of the RP3 gene resulting in a thr99-to-asn (T99N) amino acid substitution. The patient was Spanish.
Vervoort et al. (2000) identified a novel exon, ORF15, of the RPGR gene. One mutation detected in this region, found in 4 families with retinitis pigmentosa-3 (300029), was a 2-nucleotide deletion of AG at nucleotide 673 resulting in frameshift. The high frequency of mutations found in this exon suggested to Vervoort et al. (2000) that ORF15 is a mutation hotspot, with its high mutability being due to nucleotide composition (purine-rich) or repetitive nature of the sequence.
In 2 families with retinitis pigmentosa-3 (300029), Vervoort et al. (2000) identified a mutation in ORF15, a 2-bp deletion of AG at nucleotide 652.
In a family with retinitis pigmentosa-3 (300029), Vervoort et al. (2000) identified a G-to-T transversion in ORF15, an alternatively spliced 3-prime terminal exon of the RPGR gene. This mutation resulted in a glutamic acid-to-stop substitution at residue 299 of ORF15 (E299X).
In a family with X-linked cone-rod degeneration, previously reported by McGuire et al. (1995) as RP15 (300029), Mears et al. (2000) identified a 1-bp insertion, an adenine (173_174insA), causing a frameshift with insertion of 9 novel amino acids and truncation of the protein product 501 amino acids premature of the ORF15 stop codon. In this family, affected males and 'carrier' females presented with early cone involvement, which differs from the typical rod-predominant manifestation of X-linked RP.
In 2 of 3 families with X-linked cone-rod dystrophy (CORDX1; 304020), Demirci et al. (2002) demonstrated a 2-bp deletion, delGG, in ORF15 of the RPGR gene, resulting in a frameshift leading to altered amino acid structure and early termination.
Yang et al. (2002) mapped 2 Caucasian families with X-linked cone dystrophy (COD1; see 304020) to the CORDX1 locus on Xp and identified 2 distinct mutations in ORF15 of the RPGR gene. One was ORF15+1343-1344delGG and the other ORF15+694-708del15 (312610.0018).
In a family with X-linked cone-rod dystrophy (CORDX1; 304020), Demirci et al. (2002) found a 2-bp deletion, delAG, in exon 15 (ORF15) of the RPGR gene, resulting in a frameshift leading to altered amino acid structure and early termination.
Dry et al. (1999) demonstrated a splice site mutation in the RPGR gene in a family with X-linked retinitis pigmentosa with recurrent respiratory infections (300455) in which van Dorp et al. (1992) had, by electron microscopy, shown nasal ciliary abnormalities in some affected males, consisting of deficient inner dynein arms, incomplete microtubules, and disorientation of cilia, associated with recurrent respiratory infections indistinguishable from immotile cilia syndrome. Van Dorp et al. (1992) did not note whether hearing was impaired in affected individuals.
In a family with X-linked recessive atrophic macular degeneration (300834), Ayyagari et al. (2002) found that affected males had an ORF15+1164G-T mutation thought to create a novel donor splice site in the RPGR gene.
Yang et al. (2002) mapped 2 Caucasian families with X-linked cone dystrophy (see 304020) to the CORDX1 locus on Xp and identified 2 distinct mutations in ORF15 of the RPGR gene. One was ORF15+1343-1344delGG (312610.0014) and the other ORF15+694-708del15. The latter mutation was predicted to delete 5 amino acids from the C-terminal portion of the protein product.
In a family in which affected males in an X-linked recessive pedigree pattern had retinitis pigmentosa associated with impaired hearing and sinorespiratory infections (300455), Zito et al. (2003) identified a 2-bp deletion, 845delTG, in exon 8 of the RPGR gene. This frameshift mutation at residue 262 was predicted to introduce 19 new amino acids and a premature stop codon, resulting in a truncated protein of 280 residues. Carrier females and affected males in this kindred were myopic but female carriers were asymptomatic, had normal fields to confrontation, and showed sparse peripheral intraretinal pigmentation. However, additional systemic symptoms were observed in both hemizygous males and heterozygous females. One of the most striking and obvious additional features was the requirement of hearing aids by both affected males and female carriers. Both had severe recurrent ear infections from early childhood continuing into adulthood. Because of hearing loss in the high frequencies, the audiogram was considered consistent with sensorineural hearing loss, although a conductive hearing component may have contributed. Affected males and carrier females suffered from severe recurrent sinus infections. Three affected males had chronic recurrent chest infections starting in early childhood, with episodes of bronchitis, which continued into adulthood. The possibility of renal failure being part of the clinical picture was suggested by its occurrence in 1 affected male. The phenotype overlapped those described for primary ciliary dyskinesia (244400) and Usher syndrome (276900) and provided support for an essential ciliary function for RPGR in the retina and other tissues.
In 2 brothers with X-linked retinitis pigmentosa with impaired hearing and recurrent respiratory infections (300455), Iannaccone et al. (2003) identified a 576G-C transversion in a conserved region of the RPGR gene, resulting in a gly173-to-arg (G173R) substitution. The mutation was also identified in the asymptomatic mother and the symptomatic grandmother. The G173R change was not identified in more than 200 control chromosomes.
In a family with X-linked cone-rod dystrophy (304020), Ebenezer et al. (2005) found a 2 consecutive nucleotide substitutions in the ORF15 exon of the RPGR gene, 1094A-C and 1095G-T, that resulted in glu364-to-asp and glu365-to-ter amino acid substitutions, respectively (E364D/E365X).
In a family with X-linked cone-rod dystrophy (304020), Ebenezer et al. (2005) identified a G-to-T transversion at nucleotide 1176 of the ORF15 exon of the RPGR gene that resulted in a gly392-to-ter (G392X) substitution.
In a family in which a mother with retinitis pigmentosa had 2 boys with multiple ear, sinus, and respiratory infections who were diagnosed with primary ciliary dyskinesia and retinitis pigmentosa (300455), Moore et al. (2006) identified a 57-bp deletion involving the last 48 bp of exon 6 plus the following 9 bp of the adjacent intron (631-IVS6+9del) in the RPGR gene. The boys had axonemal abnormalities on electron microscopy leading to the diagnosis of primary ciliary dyskinesia; ophthalmologic examination confirmed the diagnosis of retinitis pigmentosa. Moore et al. (2006) stated that this was the first clear demonstration of X-linked transmission of primary ciliary dyskinesia.
Demirci et al. (2006) reported a 16-year-old boy with RP (300029) and bilateral Coats-like vasculopathy (see 300216) in whom they identified a 912G-T transversion in ORF15 of the RPGR gene, predicted to result in a truncated protein missing 264 amino acids at the carboxyl end. The mutation segregated with RP in the family; clinical findings in other family members, including 2 affected male patients and 3 obligate carrier females, were consistent with typical X-linked recessive RP. Because the proband was the only family member who had Coats-like exudative vasculopathy, Demirci et al. (2006) suggested that other genetic and/or environmental factors might be involved.
In a Swiss man with mild retinitis pigmentosa-3 (300029), Neidhardt et al. (2007) identified a hemizygous G-to-A transition located 363 bp downstream of exon 9 and 55 bp upstream from the exon splice acceptor site of exon 9A (g.26652G-A), resulting in increased levels of RPGR mRNA transcripts containing exon 9A. The man had night blindness since childhood and presented in his late thirties with peripheral visual impairment. The level of exon 9A expression in the patient's unaffected mother, who was heterozygous for the mutation, was normalized to 100%; the patient was found to have 180% expression levels.
In a Japanese male patient with retinitis pigmentosa (RP3; 300029), Nishiguchi et al. (2013) identified a 2-bp deletion (c.2405_2406delAG) in the RPGR gene, causing a frameshift (Glu802fs); the authors stated that this mutation had previously been described as a sufficient cause of X-linked RP by Vervoort et al. (2000). The Japanese patient also carried a heterozygous frameshift mutation in another RP-associated ciliary gene, NEK2 (604043.0001); studies in zebrafish suggested that the RPGR allele interacts in trans with the NEK2 locus to exacerbate photoreceptor defects.
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