Abnormal Rod Dark Adaptation in Autosomal Dominant Retinitis Pigmentosa With Proline-23-Histidine Rhodopsin Mutation

Kemp, Colin M.; Jacobson, Samuel G.; Román, Alejandro J.; Sung, Ching-Hwa; Nathans, Jeremy

doi:10.1016/s0002-9394(14)71529-6

Cited by 66 publications

(39 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1C) (52,72) as can be expected from the selective expression of rhodopsin in rod photoreceptors. Importantly, we demonstrated that some patients could have normal rod function, at least in some regions of the retina and at some early stages of disease (Fig.…”

Section: Discussionmentioning

confidence: 91%

Probing Mechanisms of Photoreceptor Degeneration in a New Mouse Model of the Common Form of Autosomal Dominant Retinitis Pigmentosa due to P23H Opsin Mutations

Sakami

Maeda

Bereta³

et al. 2011

Journal of Biological Chemistry

Self Cite

234

362

View full text Add to dashboard Cite

Rhodopsin, the visual pigment mediating vision under dim light, is composed of the apoprotein opsin and the chromophore ligand 11-cis-retinal. A P23H mutation in the opsin gene is one of the most prevalent causes of the human blinding disease, autosomal dominant retinitis pigmentosa. Although P23H cultured cell and transgenic animal models have been developed, there remains controversy over whether they fully mimic the human phenotype; and the exact mechanism by which this mutation leads to photoreceptor cell degeneration remains unknown. By generating P23H opsin knock-in mice, we found that the P23H protein was inadequately glycosylated with levels 1-10% that of wild type opsin. Moreover, the P23H protein failed to accumulate in rod photoreceptor cell endoplasmic reticulum but instead disrupted rod photoreceptor disks. Genetically engineered P23H mice lacking the chromophore showed accelerated photoreceptor cell degeneration. These results indicate that most synthesized P23H protein is degraded, and its retinal cytotoxicity is enhanced by lack of the 11-cisretinal chromophore during rod outer segment development.Greater understanding of a genetically heterogeneous group of retinal disorders is now possible due to the results of studies that have revealed their causative genes. Many genetic loci can cause such retinopathies (RetNet) (1). Mutations in phototransduction genes, including those in opsin genes (2), constitute one of the major known causes of inherited blinding diseases (3). Among them, retinitis pigmentosa (RP) 2 refers to a group that displays genetic heterogeneity and a range of clinical phenotypes (4). RP manifested predominantly by death of rod photoreceptor cells is a progressive disease characterized by night blindness that progresses to loss of peripheral vision and eventually all useful vision over decades (5). Of more than 100 mutant opsins associated with autosomal dominant RP (adRP), the most frequent mutation is P23H (6), accounting for ϳ10% of human cases (7,8).In vitro studies have shown that the P23H opsin associated with adRP is misfolded and retained in the ER (9 -12). Consequently, this protein is not transported to the cell membrane (12) but instead was degraded by the ubiquitin-proteosome system (13). Co-expression of adRP-linked opsin folding-deficient mutants and wild type (WT) opsin resulted in enhanced proteosome-mediated degradation and steady-state ubiquitination of both mutant and WT opsin in an experimental cell line (14). These results imply that in vivo, a misfolded monomer of P23H opsin can also induce co-aggregation with WT rhodopsin preventing rod outer segment (ROS) formation. This dominant negative effect on ROS formation has been considered as the underlying reason for the adRP inheritance of P23H in humans.The retinal structure in heterozygous transgenic mice and rats expressing the P23H opsin partially mimics that of adRP in humans carrying this mutation (15)(16)(17)(18)(19). Mislocalization of the P23H opsin in the retina also has been reported in transgenic ani...

show abstract

Section: Discussionmentioning

confidence: 91%

Probing Mechanisms of Photoreceptor Degeneration in a New Mouse Model of the Common Form of Autosomal Dominant Retinitis Pigmentosa due to P23H Opsin Mutations

Sakami

Maeda

Bereta³

et al. 2011

Journal of Biological Chemistry

Self Cite

234

362

View full text Add to dashboard Cite

show abstract

“…Of the seven human pathogenic RHO point mutations that we identified as having very prolonged recovery from light exposure (5,27,28), five are in the N-terminal and interhelical loops of the extracellular domain (Fig. 5).…”

Section: Discussionmentioning

confidence: 99%

“…RHO mutation analyses in the patients have been reported (5,27,28). Bleaching and background adaptation functions were obtained as described (5,28,29).…”

Section: Optical Coherence Tomography (Oct)mentioning

confidence: 99%

“…RHO mutation analyses in the patients have been reported (5,27,28). Bleaching and background adaptation functions were obtained as described (5,28,29). Thresholds as a function of background were fitted to the hyperbolic function T ϭ log [(I 0 n ϩ I B n )͞I 0 n ], where T is log threshold, I 0 is the background luminance that raises the threshold by 0.3 log units, I B is the background luminance, and n is the slope of the function.…”

Section: Optical Coherence Tomography (Oct)mentioning

confidence: 99%

See 1 more Smart Citation

Naturally occurring rhodopsin mutation in the dog causes retinal dysfunction and degeneration mimicking human dominant retinitis pigmentosa

Kijas

Cideciyan

Alemán

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

150

109

View full text Add to dashboard Cite

Rhodopsin is the G protein-coupled receptor that is activated by light and initiates the transduction cascade leading to night (rod) vision. Naturally occurring pathogenic rhodopsin (RHO) mutations have been previously identified only in humans and are a common cause of dominantly inherited blindness from retinal degeneration. We identified English Mastiff dogs with a naturally occurring dominant retinal degeneration and determined the cause to be a point mutation in the RHO gene (Thr4Arg). Dogs with this mutant allele manifest a retinal phenotype that closely mimics that in humans with RHO mutations. The phenotypic features shared by dog and man include a dramatically slowed time course of recovery of rod photoreceptor function after light exposure and a distinctive topographic pattern to the retinal degeneration. The canine disease offers opportunities to explore the basis of prolonged photoreceptor recovery after light in RHO mutations and determine whether there are links between the dysfunction and apoptotic retinal cell death. The RHO mutant dog also becomes the large animal needed for preclinical trials of therapies for a major subset of human retinopathies. R hodopsin, the visual pigment of rod photoreceptors, is one of many G protein-coupled receptors involved in human disease (1-3). Numerous rhodopsin gene (RHO) mutations (mostly point mutations) cause retinitis pigmentosa (RP), a blinding human retinal degeneration (see RetNet, http:͞͞ www.sph.uth.tmc.edu͞Retnet͞; refs. 4 and 5). RP caused by RHO mutations exhibits two different phenotypes (4, 5). One is an early-onset disorder with rapid loss of rods uniformly across the retina. The second has a protracted natural history of vision loss and puzzling features: rod vision can be normal early in life, and degeneration slowly spreads from a disease focus in one retinal region. Furthermore, and independent of disease stage, there is abnormally slow recovery of rod vision after bright light exposure. Variation in severity of this second phenotype may indicate that epigenetic factors play an important role in its progression (5-7) and suggests that it may be particularly amenable to preventive or ameliorative therapies.Other than in humans, naturally occurring disease-causing RHO mutations have not been identified previously in mammals. Genetically engineered animals and mutagenized flies have been the mainstay for in vivo research and treatment attempts in the past decade (reviewed in ref. 8).Naturally occurring hereditary retinal degenerations in dogs, termed progressive retinal atrophies (PRAs), are widespread and have provided several models of autosomal recessive and X-linked RP (9-13). We have now identified an autosomal dominant form of PRA, one that closely resembles the second human phenotype described above. This model should advance understanding of the pathophysiology of the disease and therapies for this major subset of dominant RP. Materials and MethodsRhodopsin Gene Sequence Analysis. Mutation analysis by comparative sequencing of the five c...

show abstract

“…The first such pathogenic rhodopsin mutation that was found, a replacement of the proline at position 23 with a histidine, or P23H, (Dryja, McGee et al 1990), is also the most common pathogenic rhodopsin mutation found among Americans. The severity of symptoms that result from the P23H mutation can vary considerably between patients (Kemp, Jacobson et al 1992;To, Adamian et al 2002), though the disease generally produces a degeneration that is both milder and progresses less quickly than some other missense mutations, especially those that cluster at the C-terminus of rhodopsin. P23H belongs to a subset of rhodopsin mutations that produces a photoreceptor degeneration that is more severe in the ventral half of the retina, thus leading to a preferential loss of the superior visual field (Heckenlively, Rodriguez et al 1991;Stone, Kimura et al 1991;Cideciyan, Hood et al 1998).…”

Section: Introductionmentioning

confidence: 99%

Xenopus laevis P23H rhodopsin transgene causes rod photoreceptor degeneration that is more severe in the ventral retina and is modulated by light

Zhang

Oglesby

Marsh-Armstrong

2008

Experimental Eye Research

View full text Add to dashboard Cite

Rhodopsin transgenes carrying mutations that cause autosomal dominant retinitis pigmentosa in humans have been used to study rod photoreceptor degeneration in various model organisms including Xenopus laevis. To date, the only transgenes shown to cause rod photoreceptor degeneration in Xenopus laevis have been either mammalian rhodopsins or chimeric versions of rhodopsin based mainly on Xenopus laevis rhodopsin sequences but with a mammalian Cterminus. Since the C-terminal sequence of rhodopsin is highly conserved in mammals and divergent in Xenopus laevis, and mammalian and epitope-tagged rhodopsins may have unexpected properties as transgenes, we decided to test whether a Xenopus laevis rhodopsin transgence carrying only the P23H mutation could also cause rod photoreceptor degeneration. Xenopus laevis tadpoles expressing these transgenes indeed had shortened outer segments and, in severely affected animals, the loss of rod photoreceptors but not the loss of cone photoreceptors. RT-PCR analyses showed that less than 10% of mutant transgenic rhodopsin relative to wild-type endogenous rhodopsin mRNA was sufficient to produce severe rod photoreceptor degeneration. As observed in other animal models as well as humans carrying this particular rhodopsin mutation, the rod photoreceptor degeneration was most severe in the ventral retina and was modified by light. Thus, the rod photoreceptor degeneration produced in Xenopus laevis by the P23H mutation in an otherwise untagged Xenopus laevis rhodopsin is generally similar to that seen with mammalian rhodopsins and epitope-tagged versions of Xenopus laevis rhodopsin, though some differences remain to be explained.

show abstract

Abnormal Rod Dark Adaptation in Autosomal Dominant Retinitis Pigmentosa With Proline-23-Histidine Rhodopsin Mutation

Cited by 66 publications

References 20 publications

Probing Mechanisms of Photoreceptor Degeneration in a New Mouse Model of the Common Form of Autosomal Dominant Retinitis Pigmentosa due to P23H Opsin Mutations

Probing Mechanisms of Photoreceptor Degeneration in a New Mouse Model of the Common Form of Autosomal Dominant Retinitis Pigmentosa due to P23H Opsin Mutations

Naturally occurring rhodopsin mutation in the dog causes retinal dysfunction and degeneration mimicking human dominant retinitis pigmentosa

Xenopus laevis P23H rhodopsin transgene causes rod photoreceptor degeneration that is more severe in the ventral retina and is modulated by light

Contact Info

Product

Resources

About