Alternative titles; symbols
HGNC Approved Gene Symbol: RPGRIP1
Cytogenetic location: 14q11.2 Genomic coordinates (GRCh38) : 14:21,280,083-21,351,301 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q11.2 | Cone-rod dystrophy 13 | 608194 | Autosomal recessive | 3 |
| Leber congenital amaurosis 6 | 613826 | Autosomal recessive | 3 |
Mutations in the retinitis pigmentosa GTPase regulator gene (RPGR; 312610) cause X-linked retinitis pigmentosa-3 (RP3), a severe, progressive, and degenerative retinal dystrophy that eventually leads to complete blindness. RPGR is ubiquitously expressed, yet mutations in the RPGR gene lead to a retina-restricted phenotype. Using the yeast 2-hybrid system, Boylan and Wright (2000) screened a bovine retina cDNA library for RPGR-interacting proteins and identified a novel protein, which they called RPGRIP1. They confirmed the specificity of the interaction between RPGR and RPGRIP1 by coimmunoprecipitation of in vitro translated protein and use of RPGR mutants. By EST database searching, Boylan and Wright (2000) identified a human homolog of the bovine gene. By PCR and 5-prime and 3-prime RACE, they isolated 2 human RPGRIP1 cDNAs, which appeared to be alternatively spliced orthologs of the bovine gene, encoding deduced proteins of 586 and 902 amino acids Dryja et al. (2001) found that the cDNA sequence in this report lacked the 5-prime end of the gene and deduced protein contains 1,259 amino acids. Boylan and Wright (2000) found that the RPGRIP1 proteins are predicted to form 2 coiled-coil domains at the N terminus, which are seen in some proteins involved in vesicular trafficking. Northern blot analysis detected a strong 2.0-kb and a weak 3.1-kb transcript in testis only. RT-PCR analysis detected strong expression of RPGRIP1 in retina, with weaker expression in testis. Roepman et al. (2000) also cloned RPGRIP1 cDNAs and identified several alternatively spliced gene products, some with retina-restricted expression, that interact specifically with RPGR in vivo and in vitro. They demonstrated that RPGR and RPGRIP1 colocalize in the outer segment of rod photoreceptors, which is in agreement with the retinitis pigmentosa phenotype observed in RP3 patients.
Hong et al. (2001) cloned the mouse ortholog of RPGRIP1. Northern blot analysis detected a retina-specific Rpgrip1 transcript of approximately 10.0 kb in wildtype mice but not in rd mice with photoreceptor degeneration (see 180072). Immunoblot analysis showed retina photoreceptor-specific expression of a 210-kD protein. Immunofluorescence and immunogold electron microscopy demonstrated localization of Rpgrip1 at the junction between the inner and outer segments, suggesting a localization in the connecting cilia. Rpgrip1 localization was the same in the absence of Rpgr, suggesting that Rpgr is anchored to the connecting cilium through its interaction with Rpgrip1. Because mouse photoreceptors are overwhelmingly rods, Hong et al. (2001) extended their localization studies to the 13-lined ground squirrel, whose photoreceptors are 95% cones. The localization of Rpgrip1 was the same, indicating that it is localized in the connecting cilia of both rod and cone photoreceptors. The authors concluded that RPGRIP1 is a structural component of the ciliary axoneme.
Gerber et al. (2001) determined that the RPGRIP1 gene encodes a predicted protein product of 1,287 amino acids.
Roepman et al. (2005) identified 2 central Ca(2+)-binding C2 domains, one of which is truncated, in RPGRIP1. The C2 domains are encoded by exons 14 to 16 and are absent from some RPGRIP1 isoforms.
Dryja et al. (2001) determined that the RPGRIP1 gene contains 25 exons.
Gerber et al. (2001) characterized the complete exon-intron structure of the RPGRIP1 gene. RPGRIP1 encompasses 24 coding exons.
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.
Castagnet et al. (2003) demonstrated the existence of RPGRIP1 isoforms with distinct cellular and subcellular localizations and biochemical properties in the retina. High mass RPGRIP1 isoforms p175/p150 were enriched in the outer segment compartment of photoreceptors. The remaining isoforms were present across subcellular fractions, including nuclei, and were soluble. The p175/p150 isoforms were predominantly sequestered in the cytoskeleton-insoluble fraction of outer segment and nuclei. In selective amacrine cells and in the transformed photoreceptor line 661W, RPGRIP1 isoforms localized at restricted foci in or near nuclear pore complexes. Among the nucleoporins, RPGRIP1 isoforms selectively associated in vivo with RAN-binding protein-2 (RANBP2; 601181). RPGRIP1 isoforms also decorated microtubules in 661W cells and occasionally formed coiled-like inclusion bodies in the perikarya. These results supported distinct but complementary functions of RPGRIP1 isoforms in cytoskeletal-mediated processes in photoreceptors and amacrine neurons. Castagnet et al. (2003) concluded that their data implicated a role of RANBP2 in the pathogenesis of neuroretinopathies and as a docking station to mediate the nucleocytoplasmic shuttling of RPGRIP1 isoforms and their interaction with other partners in amacrine and 661W neurons.
Lu and Ferreira (2005) identified expression of a novel RPGRIP1 transcript in human retina generated by use of an alternative donor splice site that leads to the skipping of 33 nucleotides from the canonical exon 13. This novel transcript is of very low abundance in retina compared with the counterpart transcript isoform expressing constitutive exons 13 and 14. The authors suggested that screening of only the constitutive exons of the RPGRIP1 gene in patients with LCA could result in underreporting of mutations, and considered it likely that translationally silent and other types of mutations, sometimes considered to be neutral polymorphisms, in the genomic region encompassing exons 12 through 14 could lead to aberrant transcripts.
In cultured mammalian cells, Shu et al. (2005) showed that both the RPGR-ORF15 isoform (312610) and RPGRIP1 localized to centrioles throughout the cell cycle, and RPGR-ORF15 and RPGRIP1 colocalized at basal bodies in cells with primary cilia.
By yeast 2-hybrid analysis, Roepman et al. (2005) determined that NPHP4 (607215) interacted with C2 domain-containing RPGRIP1 isoforms. Analysis of the interaction in the presence of Ca(2+) chelators indicated that the binding was Ca(2+) independent. NPHP1 colocalized with C2-containing RPGRIP1 isoforms in bovine and mouse retina. Mutations in NPHP4 associated with Senior-Loken syndrome-4 (606996) and mutations in RPGRP1 associated with Leber congenital amaurosis (LCA6; 613826) disrupted the interaction between the 2 proteins.
Lu et al. (2005) showed that the bovine isoforms Rpgrip1 and Rgrip1b underwent limited proteolysis constitutively in vivo in the cytoplasm compartment. This led to the relocation and accumulation of a 7-kD N-terminal domain to the nucleus, whereas the cytosolic C-terminal domain of Rpgrip1 was degraded and short-lived. Rpgrip1 mutations (605446.0007 and 605446.0008) in the RPGR-interacting domain (RID) exhibited strong cis-acting and antagonistic biologic effects on the nuclear relocation, subcellular distribution and proteolytic cleavage of Rpgrip1 and/or domains thereof. Lu et al. (2005) proposed distinct and spatiotemporal subcellular-specific roles for RPGRIP1 and further hypothesized a RPGRIP1-mediated nucleocytoplasmic crosstalk and transport pathway regulated by RID, and hence by RPGR.
By somatic cell hybrid analysis and radiation hybrid analysis, Boylan and Wright (2000) and Roepman et al. (2000) mapped the RPGRIP1 gene to chromosome 14q11. Roepman et al. (2000) suggested that the localization of RPGRIP1 at 14q11 makes it a strong candidate gene for RP16.
Leber Congenital Amaurosis 6
Dryja et al. (2001) surveyed 57 unrelated patients who had Leber congenital amaurosis for mutations in RPGRIP1 and found recessive mutations involving both alleles in 3 (6%) patients (see LCA6, 613826). All 4 mutations (605446.0001-605446.0004) created premature termination codons and are likely to be null alleles.
Gerber et al. (2001) performed direct sequencing of the 24 coding exons of the RPGRIP1 gene in 2 consanguineous families with Leber congenital amaurosis in whom a genomewide screen had detected homozygosity at the 14q11 chromosomal region. A homozygous missense mutation and a homozygous null mutation were identified in the 2 families, respectively. Among 142 unrelated LCA patients, Gerber et al. (2001) found RPGRIP1 mutations in 8 patients (5.6%). Among the 8 distinct mutations (see, e.g., 605446.0007 and 605446.0008) detected, 5 were truncating and 3 (2 missense and 1 in-frame deletion) concerned highly conserved amino acids in bovine and murine sequences.
Khan et al. (2014) performed targeted next-generation sequencing with a panel of 14 LCA genes in 23 'strictly defined' LCA patients from 19 endogamous and/or consanguineous Saudi Arabian families and identified mutations in the RPGRIP1 gene in 11 (58%) probands. Nine of the 11 were homozygous for the same founder mutation (c.1007delA; 605446.0009). Two patients with an RPGRIP1 mutation had concomitant neurodevelopmental delay.
Cone-Rod Dystrophy 13
In affected members of consanguineous Pakistani families with cone-rod dystrophy-13 (CORD13; 608194), Hameed et al. (2003) identified homozygosity for mutations in the RPGRIP1 gene (605446.0005-605446.0006).
Cone-rod dystrophy-1 (Cord1) is a recessive condition that occurs naturally in miniature longhaired dachshunds. In affected dogs, Mellersh et al. (2006) identified a 44-bp insertion in exon 2 of the Rpgrip1 gene that altered the reading frame and introduced a premature stop codon. All affected and carrier dogs within an extended inbred pedigree were homozygous and heterozygous, respectively, for the mutation. Mellersh et al. (2006) concluded that this canine disease is a model for human LCA.
Won et al. (2009) described a mouse model carrying a splice acceptor site mutation (nmf247) in the Rpgrip1 gene that is phenotypically distinct from Rpgrip1(tm1Tili) mice, which carry a null allele for the long isoform. Photoreceptor degeneration in homozygous Rpgrip1(nmf247) mice was earlier in onset and more severe than that of Rpgrip1(tm1Tili) mice. Ultrastructural studies revealed that whereas Rpgrip1(nmf247) mutants had a normal structure and number of connecting cilia, unlike Rpgrip1(tm1Tili) mice, they did not elaborate rod outer segments. Won et al. (2009) concluded that in addition to its role in outer segment disc morphogenesis, RPGRIP1 may be essential for rod outer segment formation, and that different isoforms may play different roles in photoreceptors.
Dryja et al. (2001) described a patient with Leber congenital amaurosis-6 (LCA6; 613826) who was a compound heterozygote for a 1-bp deletion (T) at codon asp1176 and a trp65-to-ter nonsense mutation (605446.0002). Both mutations led to premature termination and were likely to be null alleles.
For discussion of the trp65-to-ter (W65X) mutation in the RPGRIP1 gene that was found in compound heterozygous state in a patient with Leber congenital amaurosis-6 (LCA6; 613826) by Dryja et al. (2001), see 605446.0001.
In a patient with Leber congenital amaurosis-6 (LCA6; 613826), Dryja et al. (2001) identified homozygosity for a frameshift mutation in the RPGRIP1 gene, a 1-bp (T) insertion at codon gln893.
In a patient with Leber congenital amaurosis-6 (LCA6; 613826), Dryja et al. (2001) identified homozygosity for a frameshift mutation in the RPGRIP1 gene. The mutation consisted of a 1-bp deletion (A) at codon lys342.
In all affected members of a consanguineous Pakistani family with cone-rod dystrophy-13 (CORD13; 608194), Hameed et al. (2003) identified homozygosity for a 2480G-T transversion in exon 16 of the RPGRIP1 gene, which changed codon 827 from CGC (arg) to CTC (leu).
In 3 Pakistani families, Hameed et al. (2003) found that recessive cone-rod dystrophy (CORD13; 608194) segregated with homozygosity for a 1639G-T transversion in exon 13 of the RPGRIP1 gene, which changed codon 547 from GCT (ala) to TCT (ser).
In a patient with Leber congenital amaurosis-6 (LCA6; 613826), born to consanguineous parents of Moroccan origin, Gerber et al. (2001) identified homozygosity for an 3341A-G transition in exon 21 of the RPGRIP1 gene, resulting in an asp1114-to-gly (D1114G) substitution in the RPGR-interacting domain (RID).
Lu et al. (2005) found that the D1114G mutation abolished the interaction of RPGRIP1 in vivo with RPGR without affecting the stability of the RID and that this interaction was not resistant to stress stimuli. The D1114G mutation caused a redistribution of the processed N-terminal domain fragment of RPGRIP1 between the nuclear and cytosolic compartments.
In a French patient with Leber congenital amaurosis-6 (LCA6; 613826), Gerber et al. (2001) identified heterozygosity for a 3-bp deletion in the RPGRIP1 gene, resulting in loss of glu1279 (delE1279) located 8 residues upstream to the stop codon. The deletion was inherited from the patient's healthy father and was not identified in 252 control chromosomes. A second mutation was not identified.
Lu et al. (2005) found that the delE1279 mutation enhanced the interaction of RPGRIP1 in vivo with RPGR without affecting the stability of the RID. The interaction of delE1279 with RPGR was resistant to various stress treatments such as osmotic, pH, and heat-shock stimuli, and the delE1279 mutation caused a significant increase of the N-terminal fragment of RPGRIP1 in the cytosolic compartment.
Khan et al. (2014) performed targeted next-generation sequencing with a panel of 14 Leber congenital amaurosis (LCA) genes in 23 patients with 'strictly defined' LCA from 19 endogamous and/or consanguineous Saudi Arabian families; in 9 probands, the authors identified homozygosity for a c.1007delA (rs61751266) mutation in the RPGRIP1 gene (LCA6; 613826), resulting in a frameshift and premature termination (Glu370AsnfsTer5). Haplotype analysis was consistent with a founder effect for this mutation.
Boylan, J. P., Wright, A. F. Identification of a novel protein interacting with RPGR. Hum. Molec. Genet. 9: 2085-2093, 2000. [PubMed: 10958647] [Full Text: https://doi.org/10.1093/hmg/9.14.2085]
Castagnet, P., Mavlyutov, T., Cai, Y., Zhong, F., Ferreira, P. RPGRIP1s with distinct neuronal localization and biochemical properties associate selectively with RanBP2 in amacrine neurons. Hum. Molec. Genet. 12: 1847-1863, 2003. [PubMed: 12874105] [Full Text: https://doi.org/10.1093/hmg/ddg202]
Dryja, T. P., Adams, S. M., Grimsby, J. L., McGee, T. L., Hong, D.-H., Li, T., Andreasson, S., Berson, E. L. Null RPGRIP1 alleles in patients with Leber congenital amaurosis. Am. J. Hum. Genet. 68: 1295-1298, 2001. [PubMed: 11283794] [Full Text: https://doi.org/10.1086/320113]
Gerber, S., Perrault, I., Hanein, S., Barbet, F., Ducroq, D., Ghazi, I., Martin-Coignard, D., Leowski, C., Homfray, T., Dufier, J.-L., Munnich, A., Kaplan, J., Rozet, J.-M. Complete exon-intron structure of the RPGR-interaction protein (RPGRIP1) gene allows the identification of mutations underlying Leber congenital amaurosis. Europ. J. Hum. Genet. 9: 561-571, 2001. [PubMed: 11528500] [Full Text: https://doi.org/10.1038/sj.ejhg.5200689]
Hameed, A., Abid, A., Aziz, A., Ismail, M., Mehdi, S. Q., Khaliq, S. Evidence of RPGRIP1 gene mutations associated with recessive cone-rod dystrophy. J. Med. Genet. 40: 616-619, 2003. [PubMed: 12920076] [Full Text: https://doi.org/10.1136/jmg.40.8.616]
Hong, D.-H., Yue, G., Adamian, M., Li, T. Retinitis pigmentosa GTPase regulator (RPGR)-interacting protein is stably associated with the photoreceptor ciliary axoneme and anchors RPGR to the connecting cilium. J. Biol. Chem. 276: 12091-12099, 2001. [PubMed: 11104772] [Full Text: https://doi.org/10.1074/jbc.M009351200]
Khan, A. O., Al-Mesfer, S., Al-Turkmani, S., Bergmann, C., Bolz, H. J. Genetic analysis of strictly defined Leber congenital amaurosis with (and without) neurodevelopmental delay. Brit. J. Ophthal. 98: 1724-1728, 2014. [PubMed: 24997176] [Full Text: https://doi.org/10.1136/bjophthalmol-2014-305122]
Lu, X., Ferreira, P. A. Identification of novel murine- and human-specific RPGRIP1 splice variants with distinct expression profiles and subcellular localization. Invest. Ophthal. Vis. Sci. 46: 1882-1290, 2005. [PubMed: 15914599] [Full Text: https://doi.org/10.1167/iovs.04-1286]
Lu, X., Guruju, M., Oswald, J., Ferreira, P. A. Limited proteolysis differentially modulates the stability and subcellular localization of domains of RPGRIP1 that are distinctly affected by mutations in Leber's congenital amaurosis. Hum. Molec. Genet. 14: 1327-1340, 2005. [PubMed: 15800011] [Full Text: https://doi.org/10.1093/hmg/ddi143]
Mavlyutov, T. A., Zhao, H., Ferreira, P. A. Species-specific subcellular localization of RPGR and RPGRIP isoforms: implications for the phenotypic variability of congenital retinopathies among species. Hum. Molec. Genet. 11: 1899-1907, 2002. [PubMed: 12140192] [Full Text: https://doi.org/10.1093/hmg/11.16.1899]
Mellersh, C. S., Boursnell, M. E. G., Pettitt, L., Ryder, E. J., Holmes, N. G., Grafham, D., Forman, O. P., Sampson, J., Barnett, K. C., Blanton, S., Binns, M. M., Vaudin, M. Canine RPGRIP1 mutation establishes cone-rod dystrophy in miniature longhaired dachshunds as a homologue of human Leber congenital amaurosis. Genomics 88: 293-301, 2006. [PubMed: 16806805] [Full Text: https://doi.org/10.1016/j.ygeno.2006.05.004]
Roepman, R., Bernoud-Hubac, N., Schick, D. E., Maugeri, A., Berger, W., Ropers, H.-H., Cremers, F. P. M., Ferreira, P. A. The retinitis pigmentosa GTPase regulator (RPGR) interacts with novel transport-like proteins in the outer segments of rod photoreceptors. Hum. Molec. Genet. 9: 2095-2105, 2000. [PubMed: 10958648] [Full Text: https://doi.org/10.1093/hmg/9.14.2095]
Roepman, R., Letteboer, S. J. F., Arts, H. H., van Beersum, S. E. C., Lu, X., Krieger, E., Ferreira, P. A., Cremers, F. P. M. Interaction of nephrocystin-4 and RPGRIP1 is disrupted by nephronophthisis or Leber congenital amaurosis-associated mutations. Proc. Nat. Acad. Sci. 102: 18520-18525, 2005. [PubMed: 16339905] [Full Text: https://doi.org/10.1073/pnas.0505774102]
Shu, X., Fry, A. M., Tulloch, B., Manson, F. D. C., Crabb, J. W., Khanna, H., Faragher, A. J., Lennon, A., He, S., Trojan, P., Giessl, A., Wolfrum, U., Vervoort, R., Swaroop, A., Wright, A. F. RPGR ORF15 isoform co-localizes with RPGRIP1 at centrioles and basal bodies and interacts with nucleophosmin. Hum. Molec. Genet. 14: 1183-1197, 2005. [PubMed: 15772089] [Full Text: https://doi.org/10.1093/hmg/ddi129]
Won, J., Gifford, E., Smith, R. S., Yi, H., Ferreira, P. A., Hicks, W. L., Li, T., Naggert, J. K., Nishina, P. M. RPGRIP1 is essential for normal rod photoreceptor outer segment elaboration and morphogenesis. Hum. Molec. Genet. 18: 4329-4339, 2009. [PubMed: 19679561] [Full Text: https://doi.org/10.1093/hmg/ddp385]