Mutations in RGR, encoding a light-sensitive opsin homologue, in patients with retinitis pigmentosa

Morimura, Hiroyuki; Saindelle-Ribeaudeau, Florence; Berson, Eliot L.; Dryja, Thaddeus P.

doi:10.1038/70496

Cited by 114 publications

(85 citation statements)

References 8 publications

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“…Unlike rhodopsin, the RGR protein is coupled to all-trans-retinal that is isomerised to 11-cis-retinal upon light exposure. 23 The essential role of RGR in the process of vision was reinforced when (1) RP associated mutations in the RGR gene were described by Morimura et al 22 and (2) the phenotype of mice with targeted disruption of Rgr was described. 24 Two mutations, a number of other changes less likely to be pathogenic, and four frequent polymorphisms were found in the mutational screening of the RGR gene performed by Morimura et al, 22 which included a large group of patients with photoreceptor degeneration.…”

Section: Discussionmentioning

confidence: 99%

“…Four of these single nucleotide changes were C>T transitions, three of which corresponded to previously described frequent polymorphisms. 22 The remaining C>T substitution causing the missense change Ser241Phe was present in nine unrelated ARRP patients (eight carriers and one homozygote). Family studies in these nine ARRP families indicated that all the affected RP patients were carriers of the Ser241Phe in the four non-consanguineous pedigrees, whereas cosegregation with the disease phenotype could be excluded in the five consanguineous families.…”

Section: Rpe Retinal G Protein Coupled Receptor (Rgr)mentioning

confidence: 99%

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Study of the involvement of the RGR, CRPB1, and CRB1 genes in the pathogenesis of autosomal recessive retinitis pigmentosa

Bernal

Calaf²,

Garcia‐Hoyos³

et al. 2003

Journal of Medical Genetics

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R etinitis pigmentosa (RP), which occurs in about 1 in 3000-7000 people in Spain, is inherited in an autosomal dominant manner in 12% of cases, in an autosomal recessive way in 39%, and in an X linked manner in 4% of cases.1 This leaves 41% of RP cases with a simplex form and 4% in which the transmission pattern is unclear.The different genes that have been implicated in retinal degeneration are known or assumed to be expressed in the photoreceptor cells of the retina or in the retinal pigment epithelium (RPE). The large number of RP genes identified can be grouped into a number of functional classes: (1) proteins of the visual cascade, (2) proteins of the visual cycle, (3) photoreceptor cell transcription factors, (4) proteins related to catabolic processes, and (5) 14 and in the USH2A gene 15 have been detected in a small percentage of Spanish ARRP families. These data indicate that other genes play a part in the degeneration process of the retina in the remaining families.We analysed the involvement of three additional genes, the RPE retinal G protein coupled receptor (RGR), the cellular retinol binding protein (CRBP1), and the crumbs homologue 1 (CRB1) (table 1) in 92 ARRP Spanish families.RGR is an integral membrane protein that is expressed in the cytoplasm of RPE and Müller cells. 16 It is a member of a large family of G protein coupled receptors and shows considerable overall homology to the visual pigments and retinochromes. Under light conditions, RGR converts all-transretinal to 11-cis-retinal, whereas the reverse isomerisation occurs within rhodopsin.CRBP1 belongs to a family of cytosolic proteins whose members bind various hydrophobic ligands. This protein is a component in the retinal pigment epithelium where it is believed to function in intracellular storage and transport of retinol.The CRB1 gene is expressed in human retina and brain. It exhibits alternative splicing at its 3′ end and the four classes of mRNA are predicted to encode four different proteins, two of which are found in human retina. 17 Given its homology to the Drosophila Crumbs protein that is required for polarity and adhesion in embryonic epithelia, it has been postulated that the role of CRB1 in vertebrate photoreceptors may be in cell adhesion and photoreceptor morphogenesis. A role in localising the phototransduction complex to the apical membrane of the photoreceptors has been proposed owing to the specific expression of CRB1. MATERIALS AND METHODS FamiliesThis study comprises 92 ARRP families including four families with retinitis punctata albescens (50 consanguineous and 42 non-consanguineous pedigrees). Most of the families were examined ophthalmologically at the Hospital de la Santa Creu i Sant Pau in Barcelona or at the Fundación Jiménez Díaz in Madrid. The clinical diagnosis of RP was based on ophthalmological examination including measurements of visual acuity, ophthalmoscopy, dark adaptation, ocular tension by air tonometer, perimetry, and electroretinogram amplitudes according to ISCEV protocols. 18 METHODSBlood sam...

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Section: Discussionmentioning

confidence: 99%

Section: Rpe Retinal G Protein Coupled Receptor (Rgr)mentioning

confidence: 99%

Study of the involvement of the RGR, CRPB1, and CRB1 genes in the pathogenesis of autosomal recessive retinitis pigmentosa

Bernal

Calaf²,

Garcia‐Hoyos³

et al. 2003

Journal of Medical Genetics

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“…However, phenotypic differences exist between animals and humans carrying mutations in the same gene. For example, loss-of-function mutations in the human RPE retinal G protein-coupled receptor (RGR) gene cause RP leading to photoreceptor degeneration and blindness (93), whereas rgr −/− knockout mice show no signs of photoreceptor degeneration (94,95). A similar situation exists with recessive Stargardt macular degeneration, which causes visual loss in children (96), and abcr −/− knockout mice, where photoreceptors degenerate only very slowly (97).…”

Section: Eye Diseases Associated With Defective Metabolism Of Visual mentioning

confidence: 93%

“…More recently, RGR was suggested to activate the isomerase in a light-independent fashion (131), although no direct effect of RGR on isomerase activity was shown. Frame-shift mutations in the human RGR gene are associated with ADRP (93). Homozygous and compound-heterozygous mutations in RGR additionally have been associated with ARRP in a consanguineous Spanish family (132).…”

Section: Dominant and Recessive Rp Due To Mutations In The Rgr Genementioning

confidence: 99%

Diseases Caused by Defects in the Visual Cycle: Retinoids as Potential Therapeutic Agents

Travis

Golczak

Moise

et al. 2007

Annu. Rev. Pharmacol. Toxicol.

368

452

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Absorption of a photon by an opsin pigment causes isomerization of the chromophore from 11-cisretinaldehyde to all-trans-retinaldehyde. Regeneration of visual chromophore following light exposure is dependent on an enzyme pathway called the retinoid or visual cycle. Our understanding of this pathway has been greatly facilitated by the identification of disease-causing mutations in the genes coding for visual cycle enzymes. Defects in nearly every step of this pathway are responsible for human-inherited retinal dystrophies. These retinal dystrophies can be divided into two etiologic groups. One involves the impaired synthesis of visual chromophore. The second involves accumulation of cytotoxic products derived from all-trans-retinaldehyde. Gene therapy has been successfully used in animal models of these diseases to rescue the function of enzymes involved in chromophore regeneration, restoring vision. Dystrophies resulting from impaired chromophore synthesis can also be treated by supplementation with a chromophore analog. Dystrophies resulting from the accumulation of toxic pigments can be treated pharmacologically by inhibiting the visual cycle, or limiting the supply of vitamin A to the eyes. Recent progress in both areas provides hope that multiple inherited retinal diseases will soon be treated by pharmaceutical intervention.

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“…Nonetheless, RGR appears to play an important role. Mutations in the RGR gene cause the severe inherited blinding disease, retinitis pigmentosa (25), suggesting that RGR is required for normal functioning of the retina.…”

Section: Charles Kenneth Feldman and Jules And Doris Stein Research Tmentioning

confidence: 99%

Retinal Pigment Epithelium-Retinal G Protein Receptor-Opsin Mediates Light-dependent Translocation of All-trans-retinyl Esters for Synthesis of Visual Chromophore in Retinal Pigment Epithelial Cells

Radu¹,

Hu²,

Peng³

et al. 2008

Journal of Biological Chemistry

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Visual perception begins with the absorption of a photon by an opsin pigment, inducing isomerization of its 11-cis-retinaldehyde chromophore. After a brief period of activation, the resulting all-trans-retinaldehyde dissociates from the opsin apoprotein rendering it insensitive to light. Restoring light sensitivity to apo-opsin requires thermal re-isomerization of alltrans-retinaldehyde to 11-cis-retinaldehyde via an enzyme pathway called the visual cycle in retinal pigment epithelial (RPE) cells. Vertebrates can see over a 10 8 -fold range of background illumination. This implies that the visual cycle can regenerate a visual chromophore over a similarly broad range. However, nothing is known about how the visual cycle is regulated. Here we show that RPE cells, functionally or physically separated from photoreceptors, respond to light by mobilizing all-trans-retinyl esters. These retinyl esters are substrates for the retinoid isomerase and hence critical for regenerating visual chromophore. We show in knock-out mice and by RNA interference in human RPE cells that this mobilization is mediated by a protein called "RPE-retinal G protein receptor" (RGR) opsin. These data establish that RPE cells are intrinsically sensitive to light. Finally, we show that in the dark, RGR-opsin inhibits lecithin:retinol acyltransferase and all-trans-retinyl ester hydrolase in vitro and that this inhibition is released upon exposure to light. The results of this study suggest that RGR-opsin mediates light-dependent translocation of all-trans-retinyl esters from a storage pool in lipid droplets to an "isomerase pool" in membranes of the endoplasmic reticulum. This translocation permits insoluble all-trans-retinyl esters to be utilized as substrate for the synthesis of a new visual chromophore.The opsins include a group of light-sensitive G protein-coupled receptors. The ligand for most opsins is 11-cis-retinaldehyde (11-cis-RAL), 3 which is covalently coupled to a Lys residue in the opsins as a Schiff base. Absorption of a photon by most photoreceptor opsins isomerizes the 11-cis-RAL to all-transretinaldehyde (all-trans-RAL), inducing a conformational change that activates the G protein (transducin) and begins the visual transduction cascade (1). In the case of vertebrate photoreceptor opsins (rhodopsin and the cone opsins), the Schiff base is hydrolyzed and all-trans-RAL dissociates following photoisomerization. Restoration of light sensitivity to the resulting apo-opsin requires thermal re-isomerization of all-trans-RAL to 11-cis-RAL via a multistep enzyme pathway called the visual cycle in cells of the adjacent retinal pigment epithelium (RPE) (2) (Fig. 1). In contrast, all-trans-RAL remains covalently bound to many invertebrate opsins following photoisomerization. Here, the bound all-trans-RAL is re-isomerized in situ back to 11-cis-RAL by absorption of a second photon through a process called photoregeneration (3)(4)(5). Besides rhodopsin and the cone opsins, vertebrates contain several "nonvisual" opsins with sequence similarity...

show abstract

Mutations in RGR, encoding a light-sensitive opsin homologue, in patients with retinitis pigmentosa

Cited by 114 publications

References 8 publications

Study of the involvement of the RGR, CRPB1, and CRB1 genes in the pathogenesis of autosomal recessive retinitis pigmentosa

Study of the involvement of the RGR, CRPB1, and CRB1 genes in the pathogenesis of autosomal recessive retinitis pigmentosa

Diseases Caused by Defects in the Visual Cycle: Retinoids as Potential Therapeutic Agents

Retinal Pigment Epithelium-Retinal G Protein Receptor-Opsin Mediates Light-dependent Translocation of All-trans-retinyl Esters for Synthesis of Visual Chromophore in Retinal Pigment Epithelial Cells

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