Human Molecular Genetics

Human Molecular Genetics 2005 14(Review Issue 2):R259-R267; doi:10.1093/hmg/ddi272

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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Insights into X-linked retinitis pigmentosa type 3, allied diseases and underlying pathomechanisms

Paulo A. Ferreira^*

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

TOP ABSTRACT NEURORETINAL CIRCUITRY X-LINKED RETINITIS PIGMENTOSA... MUTATION AND TRANSCRIPTIONAL... MOLECULAR PARTNERS OF RPGR:... TRANSCRIPTIONAL HETEROGENEITY OF... GENETIC LESIONS IN RPGRIP1... SUBCELLULAR LOCALIZATION OF RPGR... ANIMAL MODELS OF RPGR... PHYSIOLOGICAL FUNCTION OF RPGR... CONCLUDING REMARKS REFERENCES

 
In the past decade, we have witnessed great advances in the identification of genes underlying numerous neurodegenerative diseases and the stark complexity determining genotype–phenotype 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 neurons—the 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

TOP ABSTRACT NEURORETINAL CIRCUITRY X-LINKED RETINITIS PIGMENTOSA... MUTATION AND TRANSCRIPTIONAL... MOLECULAR PARTNERS OF RPGR:... TRANSCRIPTIONAL HETEROGENEITY OF... GENETIC LESIONS IN RPGRIP1... SUBCELLULAR LOCALIZATION OF RPGR... ANIMAL MODELS OF RPGR... PHYSIOLOGICAL FUNCTION OF RPGR... CONCLUDING REMARKS REFERENCES

 
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 axons—the optic nerve. The lamination of the retina comprises three major neuronal (nuclear) layers with a diverse population of classes of neurons (Fig. 1) (1). The polarized, compartmentalized and ciliated (9+0) photon-capturing neurons, the photoreceptors, represent the primary sensory neurons, whose cell bodies are located in the outer nuclear layer. They consist of rod and cone photoreceptors, with the latter being further subdivided into red, green and blue cone photoreceptors (Fig. 1). The rods mediate low-acuity vision and operate under dim-light conditions, and the cones mediate color perception and high acuity vision and operate under daylight conditions. The spatial distribution and relative preponderance of the subclasses of photoreceptors across the retina confer a distinct organization to this that varies among vertebrate species (e.g. fovea, macula, etc.). Genetic lesions in photoreceptors impart distinct electrophysiological and cellular phenotypes, which are determined by what type of photoreceptor(s) is(are) primarily affected. Photoreceptors synapse with the second-order neurons, rod or cone bipolar neurons and horizontal neurons, whose cell bodies are located in the inner nuclear layer. The bipolar neurons synapse with the ganglion neurons and the synaptic input to the latter is modulated by the amacrine neurons located mainly in the inner nuclear layer. The axons of ganglion neurons coalesce and form the optic nerve, which projects into the brain (thalamus).

View larger version (35K): [in this window] [in a new window]   Figure 1. Laminar organization of the neuroretinal circuitry. The vertebrate retina is a well-defined and stratified neuronal tissue comprising several classes of the photosensory neurons—the photoreceptors (1). These are highly compartmentalized and polarized and are comprised by the OS and inner segment (IS) compartments, respectively, a cell body (nucleus, ONL) and a synaptic terminal. Photoreceptors synapse with second-order neurons, cone or rod bipolar neurons and horizontal neurons, at the outer plexiform layer. The synaptic input of these to the ganglion neurons at the inner plexiform layer is modulated by the amacrine neurons. IS, inner segments; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer; NFL, nerve fiber layer; CC, connecting cilium; H, horizontal neurons; RB, rod bipolar neurons; CB, cone bipolar neurons; A, amacrine neurons.

 

	X-LINKED RETINITIS PIGMENTOSA TYPE 3

TOP ABSTRACT NEURORETINAL CIRCUITRY X-LINKED RETINITIS PIGMENTOSA... MUTATION AND TRANSCRIPTIONAL... MOLECULAR PARTNERS OF RPGR:... TRANSCRIPTIONAL HETEROGENEITY OF... GENETIC LESIONS IN RPGRIP1... SUBCELLULAR LOCALIZATION OF RPGR... ANIMAL MODELS OF RPGR... PHYSIOLOGICAL FUNCTION OF RPGR... CONCLUDING REMARKS REFERENCES

 
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 (2,3). X-linked retinitis pigmentosa type 3 (XlRP3) (MIM312610) stands out among other RP disorders for several reasons. First, XlRP3 accounts up to 14% of all RP cases in North America, higher than any other RP locus identified to date (4). Secondly, it is considered to be the most severe form of RP, often with an onset during the first decade of life (5). Thirdly, there is a tremendous amount of allelic-dependent phenotypic expressivity and (clinical) variability in XlRP3. Mutations in XlRP3 locus are implicated in RP (4,6–10), cone–rod (11) and cone dystrophies (12) and recessive atrophic macular degeneration (13). Finally, XlRP3 is also a systemic disorder, because two distinct mutations in a highly conserved domain of retinitis pigmentosa GTPase regulator (RPGR) were linked to several non-ocular diseases such as hearing loss, sinusitis and chronic recurrent respiratory tract and ear infections (14–17).

	MUTATION AND TRANSCRIPTIONAL HETEROGENEITY OF XlRP3 AND FUNCTIONAL IMPLICATIONS

TOP ABSTRACT NEURORETINAL CIRCUITRY X-LINKED RETINITIS PIGMENTOSA... MUTATION AND TRANSCRIPTIONAL... MOLECULAR PARTNERS OF RPGR:... TRANSCRIPTIONAL HETEROGENEITY OF... GENETIC LESIONS IN RPGRIP1... SUBCELLULAR LOCALIZATION OF RPGR... ANIMAL MODELS OF RPGR... PHYSIOLOGICAL FUNCTION OF RPGR... CONCLUDING REMARKS REFERENCES

 
The human XlRP3 locus was initially identified with 19 constitutive exons and it encodes a protein, hereafter called RPGR_1–19, with a predicted molecular mass of 90 kDa (6). Exons 2–10 encode a domain, the RCC1-homologous domain (RHD), homologous to the nuclear guanine nucleotide exchange factor (GEF) of RanGTPase, RCC1, whereas the protein sequence encoded by the remaining exons exhibits no significant homology to other proteins in databases (6,8) (Fig. 2). The RHD contains the first six of the seven tandem repeats present in RCC1 (18). RPGR_1–19 has a functional, C-terminal isoprenylation motif (19). Initially, mutations found in RPGR were clustered in the RHD, but they accounted for only 20–30% 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 (5,6). No mutations were ever found in exons 16–19. Further, mutation screening of XlRP3 led to the discovery of an alternative splice exon derived from the extension of constitutive exon 15 into intron 15, upon skipping of the splicing donor site of exon 15 (9). This generates a highly purine-rich, repetitive and terminal exon, ORF15, encoding repeats with G and E residues and repeat-like sequence such as ‘EEEGEGEGE’. The resulting RPGR isoform has a predicted molecular mass of 127 kDa and it is designated hereafter as RPGR_ORF15 (Fig. 2). Strikingly, ORF15 was identified as a mutational hot spot, which accounts for the remaining XlRP3 cases (9). The ORF15 mutations comprise mostly frame-shift and/or small out-of-frame deletion mutations, but not a single missense mutation has been identified (4,9,10). Surprisingly, the ORF15 can accommodate diverse and concomitant residue changes (e.g. insertions and in-frame deletions) and still be non-pathogenic (20). This is in striking contrast to those found in the exons encoding the RHD (and up to exon 14), which consisted of all types of mutations including over 30 point mutations (missense and nonsense) and these are the most severe clinically (4,9,10,21). One of these mutations, G436D, falls well outside the RHD, implicating a functional role for putative domain(s) outside RHD and ORF15 (4). Two other mutations, G173R and 845–846delTG, within RHD (exon 8) lead intriguingly to RP and systemic phenotypes, as previously described (14,16). In contrast, ORF15 mutations have been suggested to constitute hypomorphic alleles because they are associated with milder disease states (10). Moreover, there appears to be a correlation between the location of the mutations within ORF15 and the expressivity and penetrance of the phenotype in the human (10), an observation that seems to be corroborated by dogs harboring mutations in ORF15 (22). Mutations towards the 3' end of ORF15 (and with shorter frame-shifted protein sequence) produce milder RP phenotypes (better retention of rod function). Interestingly, mutations downstream of codon 445 of ORF15 lead to preferential loss of cone function, although affecting much less rod function and hence generating cone–rod and cone dystrophies (10–12).

View larger version (11K): [in this window] [in a new window]   Figure 2. Primary structure of RPGR isoforms. RPGR1–19 is encoded by the constitutive exons 1–19 of RPGR. RPGR1–19 contains a functional, C-terminal isoprenylation site. RPGRORF15 is encoded by the constitutive exons 1–15 and intron 15. The constitutive exon 15 and intron 15 encode ORF15. The ORF15 contains a repetitive and very acidic domain (AD) and a small C-terminal basic domain (BD). The two putative and conserved GTP-binding motifs (NB) located at the N-terminus of RPGR are shown. RHD is the conserved RCC1-homologous domain and it contains six RCC1 repeats. The seventh repeat present in RCC1 is poorly conserved in RPGR (or unique to RPGR). Amino acid numbering is shown above the constructs. Note the reported numbering of ORF15 often begins with the encoded sequence of exon 15.

 
Although RPGR_1–19 and RPGR_ORF15 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 (9,23,24). These observations raise interesting questions on what are the molecular species that are physiologically and/or pathologically relevant and whether these contribute to (or confer) unique species- and tissue-specific effects. For example, the ORF15 undergoes additional and complex alternative splicing in a tissue-specific fashion (24). In the mouse, a murine RPGR_ORF15 isoform lacking an in-frame 654 bp deletion of the purine-rich repetitive region appears to rescue RPGR function in null RPGR mice (25), although intriguingly, an equivalent transgenic variant seems to exhibit a gain-of-function (26). Moreover, this truncated ORF15 variant is expressed in C57Bl/6, but not in 129/Sv, mice, because the former has a 90 bp deletion in the genomic region of ORF15 (25,26). In the mouse retina, intron 14 is not spliced out (9,23). In addition, among other variants, exons 13 and 16 appear to be capable of splicing together in the mouse and human retinas (23,24). Interestingly, an alternative and terminal exon, exon 15a (encoding only 11 residues), downstream and upstream of ORF15 and exon 16, respectively, by 6.4 and 2 kb, was reported with specific expression in the human and mouse retinas (23). A 6.4 kb deletion with proximal and distal breakpoints 1.5 kb and 70 bp downstream of exon 15 and splice donor site of exon 15a, respectively, lead to cone–rod dystrophy (CRD) in a patient (7,23). It is unclear whether a small distal segment of ORF15 is affected, but such finding would help to shed additional light on the role of ORF15 and/or exon 15a in XlRP3.

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 RPGR_1–19 and another for RPGR_ORF15 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 RPGR_1–19 and RPGR_ORF15 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 RPGR_ORF15 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

TOP ABSTRACT NEURORETINAL CIRCUITRY X-LINKED RETINITIS PIGMENTOSA... MUTATION AND TRANSCRIPTIONAL... MOLECULAR PARTNERS OF RPGR:... TRANSCRIPTIONAL HETEROGENEITY OF... GENETIC LESIONS IN RPGRIP1... SUBCELLULAR LOCALIZATION OF RPGR... ANIMAL MODELS OF RPGR... PHYSIOLOGICAL FUNCTION OF RPGR... CONCLUDING REMARKS REFERENCES

 
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) reported that the interaction of RPGR with the PDE is mediated by the RHD (amino acids 1–392) 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 RPGR_1–19 (amino acids 579–815) 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 RPGR_1–19 and/or RPGR_ORF15 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 (9,23). The interaction of 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) and it functions as a prenyl-binding protein (33). This raises the possibility that one or more RPGR isoforms may be implicated in vesicular trafficking.

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).

View larger version (27K): [in this window] [in a new window]   Figure 3. (A) Nomenclature and primary structure of RPGRIP1 isoforms. A new nomenclature is employed herein for the classification of all RPGRIP1 isoforms identified to date and derived from the alternative splicing of RPGRIP1. This classification is based on the variable primary architecture (structural/functional domains) of RPGRIP1 isoforms. RPGRIP11 is found in the bovine and human retina (formerly named b/hRPGRIP1). RPGRIP12 is like RPGRIP11 but it contains a long stretch of acidic residues between the C2 and RID domains, and it is unique to the murine. RPGRIP1 is expressed only in the murine. RPGRIP1, RPGRIP1ß, RPGRIP1, RPGRIP1 and RPGRIP1 were formerly named, respectively, mRPGRIP1b, bRPGRIP1b, bRPGRIP1c, hRPGRIP1a/b and bRPGRIP1a/hRPGRIP1d. Letters in italics note the species where expression was found (m, murine; b, bovine; h, human). RPGRIP1 has two subtypes, which differ by a short stretch of residues at the N-terminus. Numbering above the RPGRIP12 isoform refers to the residues of the human sequence delimiting the boundaries of structural/functional domains. (B) Human mutations found in RPGRIP11. Some of the human mutations identified to date and domains thereby affected are depicted. R827L causes CRD and all others lead to LCA. SMC/CC, -helical coiled coil–hinge coiled coil protein interaction motif of members of the structural maintenance of chromosomes (SMC) superfamily; C2, protein kinase C conserved region 2 and Ca2+-binding motif (C2); RID, RPGR-interacting domain; ND, nuclear domain.

 

	TRANSCRIPTIONAL HETEROGENEITY OF RPGRIP1

TOP ABSTRACT NEURORETINAL CIRCUITRY X-LINKED RETINITIS PIGMENTOSA... MUTATION AND TRANSCRIPTIONAL... MOLECULAR PARTNERS OF RPGR:... TRANSCRIPTIONAL HETEROGENEITY OF... GENETIC LESIONS IN RPGRIP1... SUBCELLULAR LOCALIZATION OF RPGR... ANIMAL MODELS OF RPGR... PHYSIOLOGICAL FUNCTION OF RPGR... CONCLUDING REMARKS REFERENCES

 
Molecular analysis of the RPGRIP1 transcripts revealed that RPGRIP1 undergoes extensive alternative splicing in the human and bovine (34,35) and, to a less extent, in the murine (36,37), and some of the splice variants are species specific (37). These observations are reminiscent to those described for RPGR. The heterogeneous splicing of RPGRIP1 leads to the production of RPGRIP1 transcript variants lacking single structural domains or combination of these. In an attempt to establish clarity and uniformity to the nomenclature of RPGRIP1 isoforms identified to date (34–38), we reclassify these into different types (and subtypes) in this review on the basis of key features of their primary structure deduced from the translation of the cognate transcripts (Fig. 3A). RPGRIP1₁ (formerly b/hRPGRIP1) contains all structural domains and it seems to be the predominant isoform in the retina of the bovine and human (34,38). RPGRIP1₂ is like RPGRIP1₁ 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). This feature is only present in the mouse and it would be interesting to find whether it confers distinct biological properties to RPGRIP1₂. RPGRIP1 formerly mRPGRIP1b) is produced from the retention of intron 13 (37). This isoform has three unique C-terminal residues, it lacks the C2 and RID domains and there are no counterparts in other species but it is the most abundant isoform in the mouse retina (37). The biological properties of RPGRIP1 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). More importantly, the role of this isoform is likely not linked to RPGR, because of the absence of RID, or to other RPGRIP1 isoforms, because it does not colocalize with these in the retina (37). RPGRIP1ß (formerly bRPGRIP1b), RPGRIP1 (formerly bRPGRIP1c) and RPGRIP1 (formerly hRPGRIP1a/b) lack the C2, comprise only the RID and contain only the C2 and RID domains, respectively (34,38). Finally, RPGRIP1 (formerly bRPGRIP1a and hRPGRIP1d) and RPGRIP1 (formerly hRPGRIP1c) are truncated at the N-terminus and, in addition, have the C2 domain deleted, respectively (34,35,38). The expression of these isoforms was established from the isolation of full-length transcripts (cDNAs) in the retina, but not all of these may have translated products in the retina. For example, antibodies against the SMC/CC domain only detect a major isoform (RPGRIP1₁) of 175 kDa in the retina (38). In contrast, a high-affinity antibody against the conserved RID of RPGRIP1 recognizes three major isoforms (including RPGRIP1₁ in the (bovine) retina, with two of these specific to the retina, and a single isoform specifically expressed in the kidney, spleen and liver (34,38). As explained subsequently, the determination of the relative protein expression levels of the various RPGRIP1 isoforms may also be hampered partly by the fact that RPGRIP1₁ undergoes limited proteolysis (38). In any event, RPGRIP1₁ 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

TOP ABSTRACT NEURORETINAL CIRCUITRY X-LINKED RETINITIS PIGMENTOSA... MUTATION AND TRANSCRIPTIONAL... MOLECULAR PARTNERS OF RPGR:... TRANSCRIPTIONAL HETEROGENEITY OF... GENETIC LESIONS IN RPGRIP1... SUBCELLULAR LOCALIZATION OF RPGR... ANIMAL MODELS OF RPGR... PHYSIOLOGICAL FUNCTION OF RPGR... CONCLUDING REMARKS REFERENCES

 
The discovery of RPGRIP1 led to the finding that genetic lesions in RPGRIP1 cause Leber's congenital amaurosis (LCA) (39–41) (Fig. 3B). LCA (MIM204000) is a genetically heterogeneous retinal dystrophy, it is the leading cause of blindness in children and it has been variably linked to several systemic phenotypes (e.g. mental retardation, nephronophthisis, etc.) (42–47). LCA is a severe retinopathy typically characterized for extinguished electroretinogram (ERG) responses normally during the first year of life (42–47). In a recent study, four distinct clinical subtypes of LCA were identified on the basis of the phenotypic variations of molecularly well-defined LCA patients (41). The phenotypic expression of patients harboring RPGRIP1 [and guanylate cyclase 2D (GUCY2D) and aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1)] mutations was synonymous to congenital or very early onset of CRD, wherein extremely strong cone dysfunction was invariably present (41). In addition, allelic mutations in RPGRIP1 and GUCY2D do not seem epistatic (41). Among the mutations found in RPGRIP1, those affecting the RID and C2 domains, are of particular interest in light of the structural/functional relevance of these domains and RPGRIP1 isoforms containing these (Fig. 3B). For example, mutations leading to small C-terminal (premature) truncations of RID and the non-conservative substitution, D1114G (39–41), are consistent with a loss-of-function of RPGRIP1, because we have shown that the complete RID domain and D₁₁₁₄ residue are critical for RPGR and RPGRIP1 interaction in vivo (34,48). An interesting mutation is the in-frame deletion of E1279 (E1279) (40). This mutation is found only in the monoallelic state and it exhibits variable penetrance, because the E1279 is found in carriers and an LCA patient (40). The molecular basis of the disease expressivity of this allele is unclear, but a recent report of ours supports that the E1279 likely represents a dominant epistatic allele (48). The RID^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). This observation is in line to that found for other photoreceptor genes with known epistatic activity, such as the retinal degeneration slow/pheripherin (RDS), the rod OS membrane protein-1 (ROM1), the cone–rod homeobox (CRX) and the GUCY2D (41,49,50). The G746E mutation (40), just upstream of the C2 domain, may likely affect the (relative) conformation of this domain and/or defines a novel domain, hence placing these with a critical physiological role in photoreceptor and retinal functions. Recently, the mutation, R827L, in the C2 domain was found to cause CRD (51), which is in concordance with the new classification proposed by Hanein et al. (41), and further implicating a role of the C2 domain in cone photoreceptors. Finally, other mutations in RPGRIP1 located upstream of these lead to premature truncations of RPGRIP1 and possibly represent null alleles (39–41).

	SUBCELLULAR LOCALIZATION OF RPGR AND RPGRIP1

TOP ABSTRACT NEURORETINAL CIRCUITRY X-LINKED RETINITIS PIGMENTOSA... MUTATION AND TRANSCRIPTIONAL... MOLECULAR PARTNERS OF RPGR:... TRANSCRIPTIONAL HETEROGENEITY OF... GENETIC LESIONS IN RPGRIP1... SUBCELLULAR LOCALIZATION OF RPGR... ANIMAL MODELS OF RPGR... PHYSIOLOGICAL FUNCTION OF RPGR... CONCLUDING REMARKS REFERENCES

 
Numerous antibodies have been generated and shared by different laboratories against unique domains of RPGR and RPGRIP1 isoforms (22,24,27,28,34,36–38,52,53). The localization of RPGR and RPGRIP1 in the retina by these antibodies, particularly within the subcellular compartments and structures of photoreceptors, appears to be ambiguous to some extent. Our laboratory has colocalized RPGR and RPGRIP1 isoforms to the OS of cone and rod photoreceptors in the human and bovine retinas, which is consistent with the disease phenotypes observed (27,34,38). These observations are also supported by the immunopurification of RPGRIP1₁ from OS, upon extensive purification of these by subcellular fractionation and confirmation of RPGRIP1₁ identity by Edman sequencing (38). The localization of RPGR to the OS has also been reported in the retina of the dog (22), human (14) and mouse (28) by other groups. In addition, a recent comprehensive proteomic analysis of the human ciliary axoneme, where over 200 of the 250 proteins residing in the axoneme were identified, failed to identify RPGR and RPGRIP1, but not RP1, as a component of the axoneme (54). In the mouse however, our studies support that RPGR is localized to the connecting cilium in the photoreceptors, whereas all but one RPGRIP1 isoform, RPGRIP1, which is specific to the mouse, are prominently, but not exclusively, localized to the connecting cilium (27,37,38). This observation is concordant to that observed by Li and coworkers (24,36,53), but they found this localization restricted solely to the connecting cilium and across species (52). In contrast to RPGR, we also find RPGRIP1 isoforms expressed in the inner retinal neurons, where they strongly localize to the perinuclear rim of the cell bodies of amacrine neurons and branching processes thereof (27,37,38). These observations are further strengthened by the identification of RPGRIP1 isoforms and/or proteolytic products thereof in homogenate of OS-depleted retinal preparations, and highly purified nuclear fractions (38).

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 ocular–renal 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

TOP ABSTRACT NEURORETINAL CIRCUITRY X-LINKED RETINITIS PIGMENTOSA... MUTATION AND TRANSCRIPTIONAL... MOLECULAR PARTNERS OF RPGR:... TRANSCRIPTIONAL HETEROGENEITY OF... GENETIC LESIONS IN RPGRIP1... SUBCELLULAR LOCALIZATION OF RPGR... ANIMAL MODELS OF RPGR... PHYSIOLOGICAL FUNCTION OF RPGR... CONCLUDING REMARKS REFERENCES

 
The canine model with mutations in ORF15 of RPGR_ORF15 (designated as XLPRA in the dog) closely mimics the human XlRP3 in terms of disease progression, severity, ERG abnormalities and cellular pathology (22,63,64). These dogs begin to exhibit defects in the organization of the OS of the rod photoreceptors, followed by their rapid fragmentation, intradiscal vesicle formation, and ultimately, neuronal death via apoptosis (64). Abnormalities in membrane turnover of OS and phagocytosis by the retina pigment epithelium are absent during the disease process (64). A mouse model with a disrupted rpgr locus has been generated and this presents retinal phenotypes that are considerably milder when compared with those observed in the human and canine (65). Interestingly, hemizygous transgenic mice with a murine-specific ORF15 variant harboring an in-frame deletion of the purine-rich region in the RPGR null background lead to a dramatic increase in the disease progression (26). This increase was not significantly prevented by the coexpression of the wild-type allele, hence suggesting that the murine ORF15 variant exerts a gain-of-function role in the retina (26). Subsequently, the same group reported the rescue of a null RPGR mouse with an equivalent transgenic and murine ORF15 construct variant, supporting that this RPGR isoform may suffice to preserve photoreceptor function (25) but raising questions on the dominant phenotypes obtained with their previous transgenic work (26).

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

TOP ABSTRACT NEURORETINAL CIRCUITRY X-LINKED RETINITIS PIGMENTOSA... MUTATION AND TRANSCRIPTIONAL... MOLECULAR PARTNERS OF RPGR:... TRANSCRIPTIONAL HETEROGENEITY OF... GENETIC LESIONS IN RPGRIP1... SUBCELLULAR LOCALIZATION OF RPGR... ANIMAL MODELS OF RPGR... PHYSIOLOGICAL FUNCTION OF RPGR... CONCLUDING REMARKS REFERENCES

 
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 RPGRIP1₁ undergoes limited proteolysis selectively in subcellular compartments of retinal neurons (38) was instrumental, in combination with the genetic data available, to probe further the biological role of RPGRIP1 and RPGR and set the stage of subsequent experiments in our laboratory. Quantitative phenotypic analysis of cells transfected with RPGRIP1₁, 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). In particular, the lack of C2 and RID from RPGRIP1 confers cytosolic localization and stability to RPGRIP1 (37,48), whereas RPGRIP1₁ and RPGRIP1ß undergo constitutive and limited proteolysis (48). This leads to the production of a stable and small N-terminal fragment (ND) that relocates to and is retained apparently in the nucleus and most prominently in the nucleolus, whereas the remaining downstream domains are short lived and remain in the cytoplasmic compartment (48). These results imply that factors interacting with the C2 and RID domains (e.g. RPGR) very likely modulate the specificity and/or activity of the limited processing and nuclear signaling pathway of RPGRIP1. This will have important implications on the role of RPGRIP1 in retinal neurons with and without expression of RPGR (or its variants). Likewise, LCA-mutations in the RID of RPGRIP1₁ 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). This latter effect is likely due to the misprocessing of RPGRIP1₁ within the SMC/CC domain, which is reflected by the accumulation of a pathological misprocessed and larger byproduct of RPGRIP1₁ 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 RPGRIP1₁ (48).

The limited proteolysis of RPGRIP1₁/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 RPGR_ORF15 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

TOP ABSTRACT NEURORETINAL CIRCUITRY X-LINKED RETINITIS PIGMENTOSA... MUTATION AND TRANSCRIPTIONAL... MOLECULAR PARTNERS OF RPGR:... TRANSCRIPTIONAL HETEROGENEITY OF... GENETIC LESIONS IN RPGRIP1... SUBCELLULAR LOCALIZATION OF RPGR... ANIMAL MODELS OF RPGR... PHYSIOLOGICAL FUNCTION OF RPGR... CONCLUDING REMARKS REFERENCES

 
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 (73,74). In any event, the RPGRIP1 interactome will unravel novel biological processes of fundamental significance to the understanding of retinal function and pathogenesis of severe and allied neurodegenerative diseases. This will pave the way for the design of novel therapeutic strategies for the treatment and/or delay the onset of these maladies, which severely impair neuronal function.

	ACKNOWLEDGEMENTS

 
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.

	REFERENCES

TOP ABSTRACT NEURORETINAL CIRCUITRY X-LINKED RETINITIS PIGMENTOSA... MUTATION AND TRANSCRIPTIONAL... MOLECULAR PARTNERS OF RPGR:... TRANSCRIPTIONAL HETEROGENEITY OF... GENETIC LESIONS IN RPGRIP1... SUBCELLULAR LOCALIZATION OF RPGR... ANIMAL MODELS OF RPGR... PHYSIOLOGICAL FUNCTION OF RPGR... CONCLUDING REMARKS REFERENCES

 

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