Disease sequence from mutant
            <i>rhodopsin</i>
            allele to rod and cone photoreceptor degeneration in man

Cideciyan, Artur V.; Hood, Donald C.; Huang, Yijun; Banin, Eyal; Li, Zongyi; Stone, Edwin M.; Milam, Ann H.; Jacobson, Samuel G.

doi:10.1073/pnas.95.12.7103

Cited by 238 publications

(222 citation statements)

References 49 publications

Supporting

Mentioning

220

Contrasting

Order By: Relevance

“…Surprisingly, a significant increase in the number of mitotic rod progenitor cells was observed in the outer nuclear layer of the transgenic fish. It has been shown in humans afflicted by RP, that as few as 25% of the original number of rods is sufficient to protect the cones from complete loss (Cideciyan, et al, 1998). Our working model is that the increased numbers of the rod progenitors in the transgenic line of zebrafish is one potential mechanism underlying the maintenance of cone function.…”

Section: Rod Degenerationmentioning

confidence: 98%

Zebrafish: A model system for the study of eye genetics

Fadool

Dowling

2008

Progress in Retinal and Eye Research

195

172

View full text Add to dashboard Cite

Over the last decade, the use of the zebrafish as a genetic model has moved beyond the proof-ofconcept for the analysis of vertebrate embryonic development to demonstrated utility as a mainstream model organism for the understanding of human disease. The initial identification of a variety of zebrafish mutations affecting the eye and retina, and the subsequent cloning of mutated genes have revealed cellular, molecular and physiological processes fundamental to visual system development. With the increasing development of genetic manipulations, sophisticated techniques for phenotypic characterization, behavioral approaches and screening strategies, the identification of novel genes or novel gene functions will have important implications for our understanding of human eye diseases, pathogenesis, and treatment.

show abstract

Section: Rod Degenerationmentioning

confidence: 98%

Zebrafish: A model system for the study of eye genetics

Fadool

Dowling

2008

Progress in Retinal and Eye Research

195

172

View full text Add to dashboard Cite

show abstract

“…; n = 19 from 12 unrelated families), was caused by mutations in RPGR. RHO mutations have been divided into two classes on the basis of psychophysical testing 19,20 . Class A mutations cause severely abnormal rod function early in life, whereas Class B mutations are compatible with functional rods either regionally (Class B1) or uniformly (Class B2) across the retina.…”

Section: Measuring Rates Of Degenerationmentioning

confidence: 99%

Lifespan and mitochondrial control of neurodegeneration

et al. 2004

View full text Add to dashboard Cite

We examine the allometric (comparative scaling) relationships between rates of neurodegeneration resulting from equivalent mutations in a diverse group of genes from five mammalian species with different maximum lifespan potentials. In both retina and brain, rates of neurodegeneration vary by as much as two orders of magnitude and are strongly correlated with maximum lifespan potential and rates of formation of mitochondrial reactive oxygen and nitrogen species (RONS). Cell death in these disorders is directly or indirectly regulated by the intrinsic mitochondrial cell death pathway. Mitochondria are the main source of RONS production and integrate cellular stress signals to coordinate the intrinsic pathway. We propose that these two functions are intimately related and that steadystate RONS-mediated signaling or damage to the mitochondrial stress-integration machinery is the principal factor setting the probability of cell death in response to a diverse range of cellular stressors. This provides a new and unifying framework for investigating neurodegenerative disorders.Cell death in inherited neurodegenerative disorders most commonly occurs by apoptosis 1-4 . The evidence is often indirect and inferred on the basis of characteristic morphological changes, such as chromatin compaction and cell shrinkage, or evidence of caspase activation, but in many cases it is more reliably based on multiple lines of evidence [1][2][3][4] . Caspase-independent cell death also occurs, although the precise mechanisms are less well understood and evidence that this occurs in inherited neurodegenerations is sparse. In these disorders, cell death occurs with a probability that is constant through part or all of the adult lifespan, consistent with a steady-state (one-hit or exponential kinetics) rather than a cumulative damage model 5,6 . The retina is a particularly well understood model of neurodegeneration. Mutations in more than 100 genes are known to cause neurodegeneration of retinal photoreceptors (RetNet; see URL below); these affect virtually all areas of metabolism and all parts of the cell 7-9 .Two main pathways lead to the activation of cysteine proteases or caspases that execute the apoptotic death program [10][11][12] . The extrinsic pathway involves cell-surface signaling complexes (e.g., Fas or FasL), which trigger the cell death cascade by activating caspase 8 and downstream caspases. The intrinsic, or mitochondrial, pathway controls activation of caspase 9, through the adaptor molecule Apaf-1, by regulating release of cytochrome c from mitochondria. Proapoptotic and antiapoptotic members of the Bcl-2 family and various stress and survival signals regulate the release of cytochrome c. Proapoptotic signals can also release proteins such as Smac and Omi, which antagonize IAP (inhibitor of apoptosis) proteins to activate cell death caspases, from the mitochondrial intermembrane space.Evidence from animal models of human photoreceptor degeneration suggests that the mitochondrial, rather than the extrinsic, cell death pa...

show abstract

“…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%

“…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%

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

149

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

Disease sequence from mutant rhodopsin allele to rod and cone photoreceptor degeneration in man

Cited by 238 publications

References 49 publications

Zebrafish: A model system for the study of eye genetics

Zebrafish: A model system for the study of eye genetics

Lifespan and mitochondrial control of neurodegeneration

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

Contact Info

Product

Resources

About