Optical Coherence Tomography (OCT) Abnormalities in rhodopsin Mutant Transgenic Swine with Retinal Degeneration

Huang, Yijun; Cideciyan, Artur V.; Alemán, Tomás S.; Banin, Eyal; Huang, Jiancheng; Syed, Nasreen A.; Petters, Robert M.; Wong, Fulton; Milam, Ann H.; Jacobson, Samuel G.

doi:10.1006/exer.1999.0793

Cited by 38 publications

(45 citation statements)

References 8 publications

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“…Scan depth was measured from the onset of the high vitread re¯ectivity (vitreoretinal interface) to the average peak of the more sclerad re¯ectivity (outer retinal choroidal complex) following alignment. Locations were identi®ed by computer algorithm (Huang et al, , 2000. To enable comparison of normal and patient data, scan depths were equated at 298 and relative thickness ( %) plotted across the retinal region.…”

Section: Discussionmentioning

confidence: 99%

“…Cross-sectional retinal re¯ectivity pro®les were obtained with optical coherence tomography (OCT; Humphrey Instruments, San Leandro, CA, U.S.A.) in one patient with concentric RP and a normal subject at the same superior retinal region. Details of the full ®eld ERG, psychophysical (kinetic perimetry and dark and light adapted static perimetry), OCT methods and data analyses have been published (Jacobson et al, 1986(Jacobson et al, , 1989(Jacobson et al, , 1997Cideciyan et al, 1998;Huang et al, 1998Huang et al, , 2000. Informed consent was given by all subjects and eye donors (see below).…”

Section: Clinical Studiesmentioning

confidence: 99%

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Concentric Retinitis Pigmentosa: Clinicopathologic Correlations

Milam

Castro

Smith

et al. 2001

Experimental Eye Research

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Progressive concentric (centripetal) loss of vision is one pattern of visual ®eld loss in retinitis pigmentosa. This study provides the ®rst clinicopathologic correlations for this form of retinitis pigmentosa. A family with autosomal dominant concentric retinitis pigmentosa was examined clinically and with visual function tests. A post-mortem eye of an affected 94 year old family member was processed for histopathology and immunocytochemistry with retinal cell speci®c antibodies. Unrelated simplex/ multiplex patients with concentric retinitis pigmentosa were also examined. Affected family members of the eye donor and patients from the other families had prominent peripheral pigmentary retinopathy with more normal appearing central retina, good visual acuity, concentric ®eld loss, normal or near normal rod and cone sensitivity within the preserved visual ®eld, and reduced rod and cone electroretinograms. The eye donor, at age 90, had good acuity and function in a central island. Grossly, the central region of the donor retina appeared thinned but otherwise normal, while the far periphery contained heavy bone spicule pigment. Microscopically the central retina showed photoreceptor outer segment shortening and some photoreceptor cell loss. The mid periphery had a sharp line of demarcation where more central photoreceptors were near normal except for very short outer segments and peripheral photoreceptors were absent. Rods and cones showed abrupt loss of outer segments and cell death at this interface. It is concluded that concentric retinitis pigmentosa is a rare but recognizable phenotype with slowly progressive photoreceptor death from the far periphery toward the central retina. The disease is retina-wide but shows regional variation in severity of degeneration; photoreceptor death is severe in the peripheral retina with an abrupt edge between viable and degenerate photoreceptors. Peripheral to central gradients of unknown retinal molecule(s) may be defective or modify photoreceptor degeneration in concentric retinitis pigmentosa.

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Section: Discussionmentioning

confidence: 99%

Section: Clinical Studiesmentioning

confidence: 99%

Concentric Retinitis Pigmentosa: Clinicopathologic Correlations

Milam

Castro

Smith

et al. 2001

Experimental Eye Research

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“…The central retinal architecture of the homozygote, at age 11, was not grossly different from that of her age-similar heterozygous sibling (Fig. 4D), although some retinal degeneration is suggested by a thinning of the highly reflective (red) signal ascribed to the outer retina (photoreceptors-RPE-anterior choroid) (22,23,33). Although many other such genotype-phenotype studies are required for clarification, the results in this LCA patient suggest better preservation of structure than function, such as has been a feature of both murine and canine RPE65-associated retinopathies at early disease stages (7,34,35).…”

Section: ϫ3mentioning

confidence: 97%

Rapid restoration of visual pigment and function with oral retinoid in a mouse model of childhood blindness

Hooser

Alemán

et al. 2000

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

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230

234

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Mutations in the retinal pigment epithelium gene encoding RPE65 are a cause of the incurable early-onset recessive human retinal degenerations known as Leber congenital amaurosis. Rpe65-deficient mice, a model of Leber congenital amaurosis, have no rod photopigment and severely impaired rod physiology. We analyzed retinoid flow in this model and then intervened by using oral 9-cis-retinal, attempting to bypass the biochemical block caused by the genetic abnormality. Within 48 h, there was formation of rod photopigment and dramatic improvement in rod physiology, thus demonstrating that mechanismbased pharmacological intervention has the potential to restore vision in otherwise incurable genetic retinal degenerations.

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“…Principles of the technique (21) and our methods (22,23) have been described. Multiple scans (4.5-or 8.0-mm-long, at various orientations) were performed to give maximal coverage of an area 9-12 mm in diameter, approximately centered on the ONH.…”

Section: Optical Coherence Tomography (Oct)mentioning

confidence: 99%

“…The individual longitudinal reflectivity profiles (LRPs) that make up each scan were allotted to 0.3 mm ϫ 0.3 mm bins based on their location. The LRPs in each bin were aligned with a dynamic cross-correlation algorithm (22,23), were median-filtered to remove speckle noise, and were averaged. The difference between the most vitreal maxima and the most scleral minima of the slope in the average LRP was used as a measure of retinal thickness at each location.…”

Section: Optical Coherence Tomography (Oct)mentioning

confidence: 99%

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.

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148

109

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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...

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Optical Coherence Tomography (OCT) Abnormalities in rhodopsin Mutant Transgenic Swine with Retinal Degeneration

Cited by 38 publications

References 8 publications

Concentric Retinitis Pigmentosa: Clinicopathologic Correlations

Concentric Retinitis Pigmentosa: Clinicopathologic Correlations

Rapid restoration of visual pigment and function with oral retinoid in a mouse model of childhood blindness

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

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