Retinitis pigmentosa: defined from a molecular point of view.
van Soest S, Westerveld A, de Jong PT, Bleeker-Wagemakers EM, Bergen AA
Department of Ophthalmogenetics, The Netherlands Ophthalmic Research Institute, Amsterdam.
Retinitis pigmentosa (RP) denotes a group of hereditary retinal dystrophies, characterized by the early onset of night blindness followed by a progressive loss of the visual field. The primary defect underlying RP affects the function of the rod photoreceptor cell, and, subsequently, mostly unknown molecular and cellular mechanisms trigger the apoptotic degeneration of these photoreceptor cells. Retinitis pigmentosa is very heterogeneous, both phenotypically and genetically. In this review we propose a tentative classification of RP based on the functional systems affected by the mutated proteins. This classification connects the variety of phenotypes to the mutations and segregation patterns observed in RP. Current progress in the identification of the molecular defects underlying RP reveals that at least three distinct functional mechanisms may be affected: 1) the daily renewal and shedding of the photoreceptor outer segments, 2) the visual transduction cascade, and 3) the retinol (vitamin A) metabolism. The first group includes the rhodopsin and peripherin/RDS genes, and mutations in these genes often result in a dominant phenotype. The second group is predominantly associated with a recessive phenotype that results, as we argue, from continuous inactivation of the transduction pathway. Disturbances in the retinal metabolism seem to be associated with equal rod and cone involvement and the presence of deposits in the retinal pigment epithelium.
Glucose transport in brain and retina: implications in the management and complications of diabetes.
Kumagai AK
Department of Internal Medicine, Michigan Diabetes Research and Training Center, University of Michigan Medical School, Ann Arbor, MI 48109-0678, USA. akumagai@umich.edu
Neural tissue is entirely dependent on glucose for normal metabolic activity. Since glucose stores in the brain and retina are negligible compared to glucose demand, metabolism in these tissues is dependent upon adequate glucose delivery from the systemic circulation. In the brain, the critical interface for glucose transport is at the brain capillary endothelial cells which comprise the blood-brain barrier (BBB). In the retina, transport occurs across the retinal capillary endothelial cells of the inner blood-retinal barrier (BRB) and the retinal pigment epithelium of the outer BRB. Because glucose transport across these barriers is mediated exclusively by the sodium-independent glucose transporter GLUT1, changes in endothelial glucose transport and GLUT1 abundance in the barriers of the brain and retina may have profound consequences on glucose delivery to these tissues and major implications in the development of two major diabetic complications, namely insulin-induced hypoglycemia and diabetic retinopathy. This review discusses the regulation of brain and retinal glucose transport and glucose transporter expression and considers the role of changes in glucose transporter expression in the development of two of the most devastating complications of long-standing diabetes mellitus and its management. Copyright 1999 John Wiley & Sons, Ltd.
Progress in measurement of ocular blood flow and relevance to our understanding of glaucoma and age-related macular degeneration.
Prog Retin Eye Res. 1999 Sep;18(5):669-87.
Mechanisms of photoreceptor death and survival in mammalian retina.
Prog Retin Eye Res. 1999 Nov;18(6):689-735.
Photoreceptor membrane proteins, phototransduction, and retinal degenerative diseases. The Friedenwald Lecture.
Molday RS
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada. molday@unixg.ubc.ca
Animal models of human retinal dystrophies.
Eye. 1998;12 ( Pt 3b):566-70.
The cone dystrophies.
Eye. 1998;12 ( Pt 3b):553-65.
Seeing beyond retinopathy in diabetes: electrophysiological and psychophysical abnormalities and alterations in vision.
Endocr Rev. 1998 Aug;19(4):462-76.
Molecular genetics of human retinal dystrophies.
Inglehearn CF
Molecular Medicine Unit, St James's University Hospital, Leeds, UK. cinglehe@hgmp.mrc.ac.uk
Retinal dystrophies are a heterogeneous group of
diseases in which the retina degenerates, leading to either partial or
complete blindness. The severe and clearly hereditary forms, retinitis
pigmentosa (RP) and various macular degenerations, affect approximately
1 in 3000 people, but many more suffer from aging macular dystrophy in
later life. Patients with RP present with narrowing visual fields and night
blindness, while those with diseases of the macula lose central vision
first. Even before the advent of molecular genetics it was evident that
these were heterogeneous disorders, with wide variation in severity, mode
of inheritance and phenotype. However, with the widespread application
of linkage analysis and mutation detection techniques, a complex underlying
pathology has now been revealed. In total, 66 distinct non-overlapping
genes or gene loci have been implicated in the various forms of retinal
dystrophy, with more being reported regularly in the literature. Within
the category of non-syndromic RP alone there are at least 22 genes (and
probably many more) involved, with further allelic heterogeneity arising
from different mutations in the same gene. This complexity presents a problem
for those involved in counselling patients, and also compounds the search
for therapies. Nevertheless, several lines of research raise the hope of
generic treatments applicable to all such patients, while the greater understanding
of normal visual function that arises from genetic studies may open up
new avenues for therapy.
Retinal regeneration in amphibians.
Mitashov VI
Kol'tsov Institute of Developmental Biology, Russian Academy of Sciences, Moscow. mitashov@ibrran.msk.su
This review is a comparative analysis of retina regeneration in different amphibians. Special attention is given to the newt, which, unlike other vertebrates, retains the capacity for the regeneration of eye structures for all life. The review focuses on the sources of the cells which contribute to retina regeneration, proliferative activity of cells participating in regeneration, the factors which control the process, and the genes expressed during the course of regeneration.
Dystrophin in the retina.
Schmitz F, Drenckhahn D
Max-Planck-Institut fur Experimentelle Medizin, Gottingen, Germany.
Dystrophin is a plasma membrane-associated cytoskeletal protein of the spectrin superfamily. The dystrophin cytoskeleton has been first characterized in muscle. Muscular 427 kDa dystrophin binds to subplasmalemmal actin filaments via its amino-terminal domain. The carboxy-terminus of dystrophin binds to a plasma membrane anchor, beta-dystroglycan, which is associated on the external side with the extracellular matrix receptor, alpha-dystroglycan, that binds to the basal lamina proteins laminin-1, laminin-2, and agrin. In the muscle, the dystroglycan complex is associated with the sarcoglycan complex that consists of several glycosylated, integral membrane proteins. The absence or functional deficiency of the dystrophin cytoskeleton is the cause of several types of muscular dystrophies including the lethal Duchenne muscular dystrophy (DMD), one of the most severe and most common genetic disorders of man. The dystrophin complex is believed to stabilize the plasma membrane during cycles of contraction and relaxation. Muscular dystrophin and several types of dystrophin variants are also present in extramuscular tissues, e.g. in distinct regions of the central nervous systems including the retina. Absence of dystrophin from these sites is believed to be responsible for some extramuscular symptoms of DMD, e.g. mental retardation and disturbances in retinal electrophysiology (reduced b-wave in electroretinograms). The reduced b-wave in electroretinograms indicated a disturbance of neurotransmission between photoreceptors and ON-bipolar cells. At least two different dystrophin variants are present in photoreceptor synaptic complexes. One of these dystrophins (Dp260) is virtually exclusively expressed in the retina. In the neuroretina, dystrophin is found in significant amounts in the invaginated photoreceptor synaptic complexes. At this location dystrophin colocalizes with dystroglycan. Agrin, an extracellular ligand of alpha-dystroglycan, is also present at this location whereas the proteins of the sarcoglycan complex appear to be absent in photoreceptor synaptic complexes. Dystrophin and dystroglycan are located distal from the ribbon-containing active synaptic zones where both proteins are restricted to the photoreceptor plasma membrane bordering on the lateral sides of the synaptic invagination. In addition, some neuronal profiles of the postsynaptic complex also contain dystrophin and beta-dystroglycan. These profiles appear to belong at least in part to projections of the photoreceptor terminals into the postsynaptic dendritic complex. In view of the abnormal neurotransmission between photoreceptors and ON-bipolar cells in DMD patients the dystrophin/beta-dystroglycan-containing projections of photoreceptor presynaptic terminals into the postsynaptic dendritic plexus might somehow modify the ON-bipolar pathway. Another retinal site associated with dystrophin/beta-dystropglycan is the plasma membrane of Muller cells where dystrophin/beta-dystroglycan appear to be present at particular high concentrations. At this location the dystrophin/dystroglycan complex may play a role in the attachment of the retina to the vitreous, and, under pathological conditions, in traction-induced retinal detachment.
The genetics of complex ophthalmic disorders.
Evans K, Bird AC
Department of Molecular Genetics, Institute of Ophthalmology, Moorfields Eye Hospital, London.
Clinical applications of fundus reflection densitometry.
Liem AT, Keunen JE, Van Norren D
F.C. Donders Institute of Ophthalmology, Academic Hospital, Utrecht, Netherlands.
Fundus reflection densitometry or retinal densitometry is a non-invasive technique to examine the visual photopigment kinetics in living eyes. The technique is based on the comparison of the reflected light from the fundus in a fully light adapted eye (when all visual photopigment has been bleached) with the reflected light following complete dark adaptation (when the retina contains its maximum amount of visual photopigment). The technique provides a measure of the density of visual photopigment, its time constant of regeneration, its distribution and spectral characteristics if measured at a series of wavelengths. Fundus reflection densitometry in the human eye was introduced 40 years ago. Presently, it is the only available technique from which direct and objective insight can be obtained into visual photopigment. This knowledge is particularly relevant in eyes where abnormalities of photoreceptor function are suspected. This paper summarizes the current knowledge of fundus reflection densitometry in the diseased and in the aging human retina, gathered over the last 30 years. Considerable improvements of the instrument for clinical purposes have been obtained, and are also discussed.
Activating mutations of rhodopsin and other G protein-coupled receptors.
Rao VR, Oprian DD
Graduate Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02254, USA.
Rhodopsin, the visual pigment of rod photoreceptors cells, is a member of the large family of G protein-coupled receptors. Rhodopsin is composed of two parts: a polypeptide chain called opsin and an 11-cis-retinal chromophore covalently bound to the protein by means of a protonated Schiff base linkage to Lys296 located in the seventh transmembrane segment of the protein. Several mutations have been described that constitutively activate the apoprotein opsin. These mutations appear to activate the protein by a common mechanism of action. They disrupt a salt-bridge between Lys296 and the couterion Glu113 that helps constrain the protein to an inactive conformation. Four of the mutations have been shown to cause two different diseases of the retina, retinitis pigmentosa and congenital night blindness. Recently, several other human diseases have been shown to be caused by constitutively activating mutations of G protein-coupled receptors.
Mechanisms of photoreceptor death and survival in mammalian retina.
Stone J, Maslim J, Valter-Kocsi K, Mervin K, Bowers F, Chu Y, Barnett N, Provis J, Lewis G, Fisher SK, Bisti S, Gargini C, Cervetto L, Merin S, Peer J
NSW Retinal Dystrophy Research Centre, Department of Anatomy and Histology, University of Sydney, Australia. jonstone@anatomy.usyd.edu.au
The mammalian retina, like the rest of the central nervous system, is highly stable and can maintain its structure and function for the full life of the individual, in humans for many decades. Photoreceptor dystrophies are instances of retinal instability. Many are precipitated by genetic mutations and scores of photoreceptor-lethal mutations have now been identified at the codon level. This review explores the factors which make the photoreceptor more vulnerable to small mutations of its proteins than any other cell of the body, and more vulnerable to environmental factors than any other retinal neurone. These factors include the highly specialised structure and function of the photoreceptors, their high appetite for energy, their self-protective mechanisms and the architecture of their energy supply from the choroidal circulation. Particularly important are the properties of the choroidal circulation, especially its fast flow of near-arterial blood and its inability to autoregulate. Mechanisms which make the retina stable and unstable are then reviewed in three different models of retinal degeneration, retinal detachment, photoreceptor dystrophy and light damage. A two stage model of the genesis of photoreceptor dystrophies is proposed, comprising an initial "depletion" stage caused by genetic or environmental insult and a second "late" stage during which oxygen toxicity damages and eventually destroys any photoreceptors which survive the initial depletion. It is a feature of the model that the second "late" stage of retinal dystrophies is driven by oxygen toxicity. The implications of these ideas for therapy of retinal dystrophies are discussed.
Photoreceptor membrane proteins, phototransduction, and retinal degenerative diseases. The Friedenwald Lecture.
Molday RS
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada. molday@unixg.ubc.ca
Eye 1998;12 ( Pt 3b):521-5
Control of rhodopsin activity in vision.
Baylor DA, Burns ME
Department of Neurobiology, Stanford University School of Medicine, CA 94305, USA.
Although rhodopsin's role in activating the phototransduction cascade is well known, the processes that deactivate rhodopsin, and thus the rest of the cascade, are less well understood. At least three proteins appear to play a role: rhodopsin kinase, arrestin and recoverin. Here we review recent physiological studies of the molecular mechanisms of rhodopsin deactivation. The approach was to monitor the light responses of individual mouse rods in which rhodopsin was altered or arrestin was deleted by transgenic techniques. Removal of rhodopsin's carboxy-terminal residues which contain phosphorylation sites implicated in deactivation, prolonged the flash response 20-fold and caused it to become highly variable. In rods that did not express arrestin the flash response recovered partially, but final recovery was slowed over 100-fold. These results are consistent with the notion that phosphorylation initiates rhodopsin deactivation and that arrestin binding completes the process. The stationary night blindness of Oguchi disease, associated with null mutations in the genes for arrestin or rhodopsin kinase, presumably results from impaired rhodopsin deactivation, like that revealed by the experiments on transgenic animals.
Receptors, photoreception and brain perception. New insights.
Mansilla AO, Barajas HM, Arguero RS, Alba CC
Division of Research and Teaching, Cardiology Hospital, National Medical Center Siglo XXI, Mexico, D.F.
Once photons have activated photosensitive cell receptors, a biochemical process mediated by G-proteins transforms the initial signal into nerve potentials. The generated impulses transmit the information through ganglion cells, after a complex interaction with other neurons by means of different neurotransmitters. Since visual function is processed in parallel, ganglion cells are divided into M-neurons which are in charge of capturing large objects, P-neurons capable of analyzing fine details and colors, and non-M, non-P neurons which are sensitive to changes in light intensity. Retina, bipolar and ganglion cells share circular receptive fields with an antagonistic surround whereas the lateral geniculate nucleus possesses rectangular receptive fields. Thus, when central cones are stimulated, ON-center cells depolarize, while OFF-center cells hyperpolarize. At the brain cortex, the magnocellular layers lead to orientation and achromatic perception, the parvocellular layers perform color vision in the blobs and achromatic contrast and orientation in the interblobs, and eventually, binocular perception is the result of multiple disparities phenomenon. On these bases, patients with agnosia for form and pattern or for depth and movement have been described. Likewise, color blindness is another disease that could be the result of photoreceptor dysfunctions or brain perception defects.
Diseases of the retina.
D'Amico DJ
Department of Ophthalmology, Harvard Medical School, Boston, MA.
Growth factor-induced retinal regeneration in vivo.
Park CM, Hollenberg MJ
Department of Pathology, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
It is apparent from a number of studies that the RPE has a remarkable ability to regenerate neural retina. While retinal regeneration from the RPE has not been reported in adult vertebrates, with the exception of the newt, there is evidence that many vertebrate species have the ability to regenerate a new neural retina during the early development. Studies of retinal regeneration in the chicken embryo have provided some insight into the requirements for this process. Recent investigations using copolymer implants as an intraocular delivery system for growth factors have demonstrated that the state of differentiation of RPE cells in the stage 22-24 chicken embryo can be altered in vivo by specific growth factors, aFGF and bFGF. These results raise the distinct possibility that variations in the local production of FGFs and their receptors in the eye during development may, in part, regulate the pathway of differentiation of RPE and neural retina precursors. Further research on the role of FGFs and their receptors in retinal development and regeneration will not only contribute to our understanding of how the differentiated state is achieved and maintained but may provide a foundation for future attempts to develop methods of treatment for various degenerative and proliferative diseases of the eye.
Advanced Coats' disease.
Haik BG
Advanced Coats' disease and retinoblastoma can both present with the triad of a retinal detachment, the appearance of a subretinal mass, and dilated retinal vessels. Thus, even the most experienced observer may not be able to differentiate these entities on ophthalmoscopic findings alone. Coats' disease is the most common reason for which eyes are enucleated with the misdiagnosis of retinoblastoma. Ultrasonography is the auxiliary diagnostic test most easily incorporated into the clinical examination, and can be utilized repeatedly without biologic tissue hazard. Ultrasonically identifiable features allowing differentiation between Coats' disease and retinoblastoma include the topography and character of retinal detachment and presence or absence of subretinal calcifications. Ultrasonography is of lesser use in poorly calcified retinoblastoma and in detecting optic nerve or extraocular extension in heavily calcified retinoblastoma. CT is perhaps the single most valuable test because of its ability to: (a) delineate intraocular morphology, (b) quantify subretinal densities, (c) identify vascularities within the subretinal space through the use of contrast enhancement, and (d) detected associated orbital or intracranial abnormalities. Optimal computed tomographic studies, however, require multiple thin slices both before and after contrast introduction and expose the child to low levels of radiation if studies are repeated periodically. MR imaging is valuable for its multiplanar imaging capabilities, its superior contrast resolution, and its ability to provide insights into the biochemical structure and composition of tissues. It is limited in its ability to detect calcium, which is the mainstay of ultrasonic and CT differentiation. Aqueous LDH and isoenzyme levels were not valuable in distinguishing between Coats' disease and retinoblastoma. The value of aqueous NSE levels in the differentiation of advanced Coats' disease and exophytic retinoblastoma deserves further study. Specimens from patients with intraocular hemorrhage should be viewed cautiously, since erythrocytes contain high levels of enolase. Analysis of subretinal aspirates is an extremely accurate method of confirming the diagnosis of Coats' disease. The key diagnostic findings are the presence of cholesterol crystals and pigment-laden macrophages and the absence of tumor cells on fresh preparations. The technique should be reserved for patients where retinoblastoma has been ruled out by all noninvasive means and massive subretinal drainage is anticipated. The natural progression in advanced Coats' disease is toward the development of a blind, painful eye. Spontaneous regression does rarely occur, and some eyes quietly progress to a phthisical state.