Insights into X-linked retinitis pigmentosa type 3, allied diseases and underlying pathomechanisms
Departments of Ophthalmology and Molecular Genetics and Microbiology, Duke University Medical Center, Erwin Road, Durham, NC 27710, USA
* To whom correspondence should be addressed. Tel: +1 919-684-8457; Fax: +1 919-684-3826; Email: ferre044{at}mc.duke.edu
Received May 6, 2005; Accepted August 1, 2005
| ABSTRACT |
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In the past decade, we have witnessed great advances in the identification of genes underlying numerous neurodegenerative diseases and the stark complexity determining genotypephenotype relationships that lead to the impairment, and ultimately, premature death of neurons. However, significant challenges lie ahead in understanding the pathobiological and spatiotemporal processes triggered by genetic lesions underlying neurodegenerative disorders. Neuroretinal dystrophies occupy a prominent place among neurodegenerative diseases, because of the large number and prevalence of disease-causing genes, the diverse functions, the wealth of allelic, non-allelic and clinical heterogeneities determining the phenotypic expressivity and penetrance of the disease and the ease of use of animal models to probe gene function and disease pathogenesis in a well-defined neuroretinal circuitry. Retinitis pigmentosa (RP) has a prevalence of about one in 4000. RP is a retinal dystrophy leading primarily to the progressive death of photon-capturing neuronsthe rod photoreceptors. X-linked retinitis pigmentosa type 3 (XlRP3) accounts up to 14% of all RP cases, higher than any other single RP locus identified to date, and considered to be the most severe of all RP cases. The XlRP3 encodes the retinitis pigmentosa GTPase regulator (RPGR). RPGR interacts with the RPGR interacting protein-1 (RPGRIP1). Mutations in RPGRIP1 cause Leber's congenital amaurosis. This review highlights the progress devoted to understand the pathogenesis associated with XlRP3 and allied disorders and, concepts, trends and discrepancies emerging as molecular, subcellular and physiological processes linked to RPGR and RPGRIP1-protein network begin to be elucidated, and that may serve as a paradigm for other biological processes and neurodegenerative diseases.
| NEURORETINAL CIRCUITRY |
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The retina is a stratified neuronal tissue that lines the posterior eyecup. The retina is an integral part of the central nervous system but it is often portrayed as an appendix organ of the brain in light of its distant connection via a dense bundle of axonsthe optic nerve. The lamination of the retina comprises three major neuronal (nuclear) layers with a diverse population of classes of neurons (Fig. 1) (1
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| X-LINKED RETINITIS PIGMENTOSA TYPE 3 |
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RP is a genetically heterogeneous disease affecting primarily the rod photoreceptor neurons, although cone photoreceptors are affected subsequently by the loss of rod photoreceptors and die, hence leading to complete blindness (2
| MUTATION AND TRANSCRIPTIONAL HETEROGENEITY OF XlRP3 AND FUNCTIONAL IMPLICATIONS |
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The human XlRP3 locus was initially identified with 19 constitutive exons and it encodes a protein, hereafter called RPGR119, with a predicted molecular mass of 90 kDa (6
2030% of patients with XlRP3, a frequency at odds with the linkage data analysis, which supported that XlRP3 is responsible for about two-thirds of XlRP (5
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Although RPGR119 and RPGRORF15 transcripts represent two splice variants shown to have translated products in the retina and elsewhere (but the apparent molecular masses appear to differ among laboratories), transcriptional studies indicate that the XlRP3 locus is subjected to an exceptionally high degree of complex and heterogeneous splicing, mostly downstream of RHD, and some splice variants are species and tissue specific (9
90 bp deletion in the genomic region of ORF15 (25
6.4 and 2 kb, was reported with specific expression in the human and mouse retinas (23
In contrast to the transcriptional variants identified, far fewer RPGR isoforms have been detected at protein level. Our laboratory has detected only one major isoform for RPGR119 and another for RPGRORF15 in the human retina, with antibodies specific towards unique domains of these (27
). Another antibody against the conserved and complete RHD also detects only two isoforms in lymphoblasts, which are absent in patients with truncations, Q236X and 468:RNQIICX, but not with the 6.4 kb deletion of intron 15, as previously described (P.A. Ferreira, unpublished data). In addition, equivalent RPGR isoforms appear to exhibit differences in molecular masses, depending on whether they are ectopically expressed in the retina or transfected cells (24
,26
). Observations like these appear to be supported by reports from other laboratories, independent of the apparent discrepancies in molecular masses (22
,24
,28
). Altogether, it is likely that many of the splice variants are not translated (biologically relevant) and that the ORF15 plays a dual role by modulating the proposed splicing efficiency (e.g. exonic splicing enhancer) (24
) of this genomic region, although concomitantly causing the production of pathogenic protein variants and a change in the ratio between the RPGR119 and RPGRORF15 isoforms upon genetic lesions. Differences in the structure of the constitutive intron 15 among species may also determine the ratio of these isoforms between species, production of novel RPGRORF15 isoforms that contribute to unique species-specific phenotypes and significant differences in the phenotypic penetrance observed between the human/dog and the murine species. The effect of mutations in changing the ratio of protein isoforms is known to occur in other genes such as the MAPT gene, which is implicated in frontotemporal dementia with parkinsonism (FTDP-17) (29
,30
).
MOLECULAR PARTNERS OF RPGR: PDE AND RPGRIP1
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To elucidate the molecular pathogenesis of XlRP3 and the function of RPGR, several groups set out independently to find molecular partners of RPGR. The
PDE was the first RPGR partner identified from a yeast two-hybrid screen. Linari et al. (31
PDE is mediated by the RHD (amino acids 1392) of RPGR and the few human missense mutations tested in RHD impaired its interaction with
PDE in vitro and in vivo. Although the C-terminal domain of RPGR119 (amino acids 579815) failed to interact with
PDE, this construct lacked about 190 residues located between the RHD and C-terminal domains tested. A number of questions remain unanswered to impart biological relevance to these findings. In particular, it needs elucidation whether
PDE is a natural partner of RPGR119 and/or RPGRORF15 and whether these colocalize in photoreceptors. Finally, no human mutations were found in the ubiquitously expressed
PDE to date and the findings fail to explain the basis of the retina-specific effects of genetic lesions in XlRP3 locus, because the RPGR isoforms are also expressed across several tissues (9
PDE with RPGR may be significant in light of the findings that the
PDE associates with the GTPase, Rab13, to retrieve this from the cell membranes (acting similar to a GDP-dissociation inhibitor) (32
Subsequently, we reported the isolation of a novel partner for RPGR, RPGR interacting protein-1 (RPGRIP1) (34
), from yeast two-hybrid screenings, a finding independently corroborated by two other groups (35
,36
). In contrast to
PDE (and RPGR), RPGRIP1 is predominantly expressed in the retina of the human, bovine and mouse (albeit restricted expression of specific isoforms is found also in other tissues), thus leading to a rational for the mainly retina-restricted effects of mutations in RPGR (34
). With the exception of another protein with unknown function in the GenBank database (NM_015272
[GenBank]
/KIAA1005) (34
), RPGRIP1 does not exhibit strong overall homologies to other proteins. RPGRIP1 consists of N-terminal and coiled coil domains followed by a C2 domain and a C-terminal RPGR-interacting domain (RID) (Fig. 3A). Mutations in RHD of RPGR abolish its interaction with RID of RPGRIP1 in vivo (34
,35
). RPGR and RPGRIP1 form a complex in vivo in the retina, partially colocalize to the outer segment (OS) compartment of photoreceptors, and associate directly with each other in vitro (27
,34
).
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| TRANSCRIPTIONAL HETEROGENEITY OF RPGRIP1 |
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Molecular analysis of the RPGRIP1 transcripts revealed that RPGRIP1 undergoes extensive alternative splicing in the human and bovine (34
1 (formerly b/hRPGRIP1) contains all structural domains and it seems to be the predominant isoform in the retina of the bovine and human (34
2 is like RPGRIP1
1 with the exception of an insertion of a long acidic poly(E) (glutamate) stretch of about 80 residues between the C2 and RID domains (36
2. RPGRIP1
formerly mRPGRIP1b) is produced from the retention of intron 13 (37
appear distinct from all other isoforms because of its unique subcellular distribution in the retina and cultured cells. It is found only in the cytosolic compartment, where it partially colocalizes with a subpopulation of lysosomes (discussed subsequently) (37
(formerly bRPGRIP1c) and RPGRIP1
(formerly hRPGRIP1a/b) lack the C2, comprise only the RID and contain only the C2 and RID domains, respectively (34
(formerly bRPGRIP1a and hRPGRIP1d) and RPGRIP1
(formerly hRPGRIP1c) are truncated at the N-terminus and, in addition, have the C2 domain deleted, respectively (34
1) of
175 kDa in the retina (38
1 in the (bovine) retina, with two of these specific to the retina, and a single isoform specifically expressed in the kidney, spleen and liver (34
1 undergoes limited proteolysis (38
1 is highly enriched in the OS compartment of the photoreceptor neurons and may be the only RPGRIP1 isoform expressed in these neurons (38| GENETIC LESIONS IN RPGRIP1 CAUSE LEBER'S CONGENITAL AMAUROSIS |
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The discovery of RPGRIP1 led to the finding that genetic lesions in RPGRIP1 cause Leber's congenital amaurosis (LCA) (39
E1279) (40
E1279 is found in carriers and an LCA patient (40
E1279 likely represents a dominant epistatic allele (48
E1279 exhibits in vivo stronger binding activity towards RPGR than wild-type RID, and in contrast to this, it is extremely tolerant to physicochemical stresses (48| SUBCELLULAR LOCALIZATION OF RPGR AND RPGRIP1 |
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Numerous antibodies have been generated and shared by different laboratories against unique domains of RPGR and RPGRIP1 isoforms (22
1 from OS, upon extensive purification of these by subcellular fractionation and confirmation of RPGRIP1
1 identity by Edman sequencing (38
, which is specific to the mouse, are prominently, but not exclusively, localized to the connecting cilium (27
We have proposed that the apparent and partial discrepancies for the localization of RPGR and RPGRIP1 in the photoreceptors may reflect known variations in the structural organization of the OS of photoreceptors among species (rodents versus other ciliated species) and contribute to variations of disease expressivity of genetic lesions in RPGR and possibly, RPGRIP1, among species (discussed subsequently) (27
). Likewise, expression of RPGRIP1 in inner retina neurons may underlie the distinct phenotypes observed in patients with mutations in RPGR and possibly in RPGRIP1. Hence, the genetic variations among the RPGR and RPGRIP1 genes, the unique features of the cognate proteins described previously, the variations in isoform ratios and species-specific expression of some of these may underlie the molecular basis for some of the unique structural and circuitry organization of retinal neurons among species and prove to constitute excellent molecular tools to probe further these distinct variations. Finally, the systemic phenotype (e.g. progressive hearing loss) linked to specific allelic mutations in XlRP3 is concordant with RPGR localization in non-ciliated cochlear tissues (14
) and hints towards an enhanced effect of these mutations in cell function. Altogether, the localization results mentioned earlier are reminiscent to the apparently discrepant localization results obtained for the complex subcellular distribution pattern of polycystin-1 (PKD1) (55
), which is implicated in autosomal dominant polycystic kidney disease (ADPKD) (56
), and that has been localized to the cilium (57
) and to several membrane domains (55
,58
,59
). In this regard, it is interesting to note that ocularrenal phenotypes may also be linked to RPGR and RPGRIP1 (60
) (R. Roepman, unpublished data). The complex subcellular distribution pattern observed for PKD1 extends also to other proteins such as
PDE (61
) and nephrocystin-4 (62
), with
PDE having also varied subcellular localization between species (61
).
| ANIMAL MODELS OF RPGR AND RPGRIP1 |
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The canine model with mutations in ORF15 of RPGRORF15 (designated as XLPRA in the dog) closely mimics the human XlRP3 in terms of disease progression, severity, ERG abnormalities and cellular pathology (22
A mouse model harboring a disrupted rpgip1 locus has also been reported (53
). In contrast to rpgr ko model, these exhibit extremely severe and very early dysplasia of the OS compartment of rod photoreceptors and expansion of their disks (53
). Like with the null and transgenic rpgr mouse models (26
,65
), no ultrastructural defects were observed in the connecting cilium of rpgip1/ mice (53
), a ultrastructural phenotype observed in 97% of genetic lesions leading to primary ciliary dykinesia (immotile cilia syndrome) (66
). Moreover, a strong word of caution should be noted in interpreting the phenotypes obtained with the rpgip1/ mice (53
). These arouse from the partial homologous recombination of the right arm of the recombination construct and insertion (instead of homologous recombination) of the left arm, comprising exons 4 and 5, downstream of exon 13 of the rpgrip1 locus (the numbering of murine exons described herein assumes the translation initiation codon in exon 1 for the sake of consistency to that described for the human gene). Hence, it is likely that exon 13 splices with out-of-phase exons 4 and 5, and this may contribute to off-target phenotypes. In addition, the expression of the 63 kDa and murine-specific RPGRIP1
isoform is likely not affected (37
). To this end, new genetically targeted rpgrip1 null models will be required to establish the role of the various RPGRIP1 isoforms, mutations therein and epistatic interactions, in retinal and photoreceptor function and possibly in syndromic phenotypes.
| PHYSIOLOGICAL FUNCTION OF RPGR AND RPGRIP1 |
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Although a wealth of information has been collected with the clinical/phenotypic characterization of genetic lesions in RPGR and RPGRIP1, the role of these in molecular and subcellular processes underlying photoreceptor and retinal function and the pathogenesis of (neuroretinal) disorders linked to RPGR and RPGRIP1 remains elusive. In an attempt to bridge this gap, the findings suggesting that RPGRIP1
1 undergoes limited proteolysis selectively in subcellular compartments of retinal neurons (38
1, RPGRIP1ß and RPGRIP1
(Fig. 3A) supported that the combination of the C2 and RID domains determined the subcellular localization and fate of the RPGRIP1 and domains thereof (48
(37
1 and RPGRIP1ß undergo constitutive and limited proteolysis (48
1 strongly affect the biological properties of RPGRIP1. A LCA and frame-shift mutation (Q893X) leading to the premature truncation of RID enhance dramatically the localization of ND solely to the nuclear compartment, whereas the D1114G mutation completely abolishes the immunoreactivity of the SMC/CC domain towards two cognate antibodies in the cytosol compartment (48
1 within the SMC/CC domain, which is reflected by the accumulation of a pathological misprocessed and larger byproduct of RPGRIP1
1 containing the ND. Finally, the dominant
E1279 mutation causes a significant increase in the retention of ND in the cytosolic compartment and interestingly, it leads to a decrease in the electrophoretic mobility of the unprocessed RPGRIP1
1 (48
The limited proteolysis of RPGRIP1
1/ß is reminiscent to the regulated intermembrane proteolysis of several proteins (67
), such as PKD1 (55
,68
), which C-terminus translocates to the nucleus upon proteolytic cleavage to activate the AP-1 pathway (55
). In addition, LCA-linked mutations in RPGRIP1 may share pathomechanisms to various diseases, wherein the pathological relocation to the nucleus of misprocessed proteolytic fragments underlies the molecular pathogenesis of neurodegenerative (69
,70
) and other diseases (71
,72
). Altogether, these data raise a new set of questions. Among these, it will be of particular importance to address the identity of the components and signaling mechanisms/pathways that mediate (i) the limited proteolytic processing of RPGRIP1, (ii) the retention and role of the unprocessed RPGRIP1 in the cytosolic compartment, (iii) the nuclear translocation of the ND from the cytosolic compartment to components of the nuclear pore complexes (e.g. RanBP2) and from these to the nucleoli and (iv) its function in the nucleolus (e.g. mode of gene regulation). In addition, the effect(s) of human RPGR/RPGRIP1 mutations in these processes will be critical to further understand the disease pathomechanisms linked to the cognate genes. Recently, nucleophosmin, a nucleocytoplasmic shuttling and multifunctional molecular chaperone with nucleolar localization in interphasic cells, was found to interact with RPGRORF15 through its small C-terminal basic domain (Fig. 2) (28
), hence raising the possibility that it could act as a chaperone for the nuclear translocation of ND of RPGRIP1. In any event, novel partners identified towards the ND and SMC/CC domains of RPGRIP1 and the generation of RPGRIP1 mouse models are bound to provide new insights into the role of the RPGRIP1 interactome in retinal function and disease (unpublished data).
| CONCLUDING REMARKS |
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The RPGR and RPGRIP1 genes are likely to represent additional targets of positive selection during evolution and contribute to variations in the retina among species. To this effect, they join a growing list of evolving genes determining human traits, disease phenotypes and allied pathogenic processes and therapeutic efficacies (73
| ACKNOWLEDGEMENTS |
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In light of space constraints, the author apologizes for not referencing many reports from other colleagues, who contributed for the mutation analysis of XlRP3 and LCA. This work was supported by grants NIH EY11993 and EY012665 to P.A.F. P.A.F. is the Jules and Doris Stein Research to Prevent Blindness Professor.
Conflict of Interest statement. None declared.
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