Disease relevance of RPGR

• We determined the mutation spectrum of the RP2 and RPGR genes in patients with X-linked retinitis pigmentosa (XLRP) and searched for correlations between categories of mutation and severity of disease [1].
• These results suggest that RPGR mutations give rise to retinal degeneration by dysregulation of intracellular processes that determine protein localization and protein transport [2].
• Retinal disease phenotypes in patients with mutations in the RPGR-ORF15 were more severe than in patients with mutations in RP2 or other regions of the RPGR [3].
• The comparable region of the human X chromosome includes the disease locus for RP3, an X-linked form of retinitis pigmentosa, although the current canine disease interval is much larger [4].
• Two families (1%) have a pathogenic RPGR mutation, indicating that families with apparent autosomal transmission of RP may actually have X-linked genetic disease [5].

Psychiatry related information on RPGR

• Patient BB was thought to have RP because of a lesion at the RP3 locus, in addition to chronic granulomatous disease, Duchenne muscular dystrophy (DMD), mild mental retardation, and the McLeod phenotype [6].
• The Clinical Dementia Rating (CRD), a global rating device, was developed for a prospective study of mild senile dementia--Alzheimer type (SDAT) [7].

High impact information on RPGR

• Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin [8].
• Mutational hot spot within a new RPGR exon in X-linked retinitis pigmentosa [9].
• Because the mutations in the remainder of the XLRP patients may reside in undiscovered exons of RPGR, we sequenced a 172-kb region containing the entire gene [9].
• The gene RPGR was previously identified in the RP3 region of Xp21.1 and shown to be mutated in 10-20% of patients with the progressive retinal degeneration X-linked retinitis pigmentosa (XLRP) [9].
• The RP3 gene was recently isolated by positional cloning, whereas the RP2 locus was mapped genetically to a 5-cM interval [10].

Chemical compound and disease context of RPGR

• X-linked retinitis pigmentosa in two families with a missense mutation in the RPGR gene and putative change of glycine to valine at codon 60 [11].
• PURPOSE: The retinitis pigmentosa guanosine triphosphatase (GTPase) regulator (RPGR) is essential for photoreceptor survival [12].
• Patients who fail the test (peak Cr >/=2 mg/dL during the first postoperative week) as well as the patients with diabetes mellitus are at increased risk of CRD [13].

Biological context of RPGR

• The two intragenic deletions, two nonsense and three missense mutations within conserved domains provide evidence that RPGR (retinitis pigmentosa GTPase regulator) is the RP3 gene [14].
• 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 [15].
• 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 RCC-1 protein (a guanine nucleotide-exchange factor for Ran-GTPase) [16].
• 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 [1].
• However, mouse models null for RPGR had, surprisingly, a very mild phenotype compared with those observed in XlRP3-affected humans and dogs [17].

Anatomical context of RPGR

• We show that nephrocystin-5, RPGR and calmodulin can be coimmunoprecipitated from retinal extracts, and that these proteins localize to connecting cilia of photoreceptors and to primary cilia of renal epithelial cells [8].
• Previously published work showed that both proteins, RPGR and RPGRIP1, are present in the ciliary structure that connects the inner and outer segments of rod and cone photoreceptors [18].
• 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 [19].
• These data suggest that RPGRIP is a structural component of the ciliary axoneme, and one of its functions is to anchor RPGR within the cilium [20].
• Leukocyte genomic DNA samples were obtained and screened for RPGR (RP3) mutations by direct polymerase chain reaction sequencing [21].

Associations of RPGR with chemical compounds

• In a yeast two-hybrid screen we identified the delta subunit of rod cyclic GMP phosphodiesterase (PDEdelta) as interacting with the RCC1-like domain (RLD) of RPGR (RPGR392) [2].
• Complex expression pattern of RPGR reveals a role for purine-rich exonic splicing enhancers [22].
• Sequence analysis of the RPGR gene identified a single base pair change, a G-->T transversion, that converts codon 52 GGA (Gly) to TGA (stop codon); the mutation segregates with the disease [23].
• CONCLUSIONS: A mutation in exon 3 of the RPGR gene, which would result in a putative glycine to valine substitution at codon 60, is associated with a severe clinical phenotype in male patients and a patchy retinopathy without a tapetal-like reflex in carrier females [11].
• In contrast, the much narrower binding specificity of selectin cell adhesion molecules results from an extended binding site within a single CRD [24].

Physical interactions of RPGR

• RPGR interacts with the RPGR interacting protein-1 (RPGRIP1) [25].
• RPGRIP1 encodes the retinitis pigmentosa GTPase interacting protein 1 and interacts with RPGR, the latter represents the major X-linked RP (XRRP) gene, as it accounts for 70-80% of the XRRP patients and up to 13% of all RP patients [26].

Other interactions of RPGR

• The COD1 locus originally was localized, by the study of three independent families, to a region between Xp11.3 and Xp21.1, encompassing the retinitis pigmentosa (RP) 3 locus [27].
• RESULTS: Screening of 58 xlRP families revealed RP2 mutations in 8% and RPGR mutations in 71% of families with definite X-linked inheritance [28].
• Six of these mutations were detected in the conserved amino-terminal region of RPGR protein, containing tandem repeats homologous to the RCC1 protein, a guanine nucleotide-exchange factor for Ran-GTPase [29].
• Because mutations in the RPGR gene to date account for disease in only a small proportion of RP3 families, the possibility that this new locus (CSNB4) also segregates with an as yet unidentified XLRP locus cannot be excluded [30].
• 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 [28].

Analytical, diagnostic and therapeutic context of RPGR

• The specificity of the interaction was confirmed by co-immunoprecipitation of in vitro translated protein and using RPGR mutants [31].
• PCR amplification and Southern blot analysis revealed the absence of the 5' half of the RPGR gene [32].
• Reverse transcription-polymerase chain reaction (RT-PCR) was performed by using the primers flanking exon 2 of RPGR transcript, followed by gel purification and direct sequencing [33].
• Comparative northern blot hybridization of ubiquitous and tissue-specific RPGR probes identified high molecular weight transcripts with similar expression patterns in both human and mouse [34].
• Identification of an RPGR mutation in atrophic maculardegeneration expands the phenotypic range associated with this gene and provides a new tool for the dissection of the relationship between clinically different retinal pathologies [35].

References