Retinal pigment epithelial cells (RPE) constitute a simple layer of cuboidal cells that are strategically situated behind the photoreceptor (PR) cells. The inconspicuousness of this monolayer contrasts sharply with its importance [1]. The relationship between the RPE and PR cells is crucial to sight; this is evident from basic and clinical studies demonstrating that primary dysfunctioning of the RPE can result in visual cell death and blindness. RPE cells carry out many functions including the conversion and storage of retinoid, the phagocytosis of shed PR outer segment membrane, the absorption of scattered light, ion and fluid transport and RPE-PR apposition. The magnitude of the demands imposed on this single layer of cells in order to execute these tasks, will become apparent to the reader of this review as will the number of clinical disorders that take origin from these cells.

/pdf/the-retinal-pigment-epithelium-in-health-and-disease-lqofq6e2p6.pdf

The Retinal Pigment Epithelium in Health and Disease

Exceptional progress has been made during the past two decades in identifying genes causing inherited retinal diseases such as retinitis pigmentosa. An inescapable consequence is that the relationship between genes, mutations, and clinical findings has become very complex. Success in identifying the causes of inherited retinal diseases has many implications, including a better understanding of the biological basis of vision and insights into the processes involved in retinal pathology. From a clinical point of view, there are two important questions arising from these developments: where do we stand today in finding disease-causing mutations in affected individuals, and what are the implications of this information for clinical practice? This perspective addresses these questions specifically for retinitis pigmentosa, but the observations apply generally to other forms of inherited eye disease.

https://jamanetwork.com/journals/jamaophthalmology/articlepdf/817220/esa60014.pdf

Perspective on Genes and Mutations Causing Retinitis Pigmentosa

Absorption of a photon by an opsin pigment causes isomerization of the chromophore from 11-cis-retinaldehyde to all-transretinaldehyde. 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.

Diseases caused by defects in the visual cycle: retinoids as potential therapeutic agents.

Myopia, or nearsightedness, is the most common eye disorder, resulting primarily from excess elongation of the eye. The etiology of myopia, although known to be complex, is poorly understood. Here we report the largest ever genome-wide association study (45,771 participants) on myopia in Europeans. We performed a survival analysis on age of myopia onset and identified 22 significant associations (), two of which are replications of earlier associations with refractive error. Ten of the 20 novel associations identified replicate in a separate cohort of 8,323 participants who reported if they had developed myopia before age 10. These 22 associations in total explain 2.9% of the variance in myopia age of onset and point toward a number of different mechanisms behind the development of myopia. One association is in the gene PRSS56, which has previously been linked to abnormally small eyes; one is in a gene that forms part of the extracellular matrix (LAMA2); two are in or near genes involved in the regeneration of 11-cis-retinal (RGR and RDH5); two are near genes known to be involved in the growth and guidance of retinal ganglion cells (ZIC2, SFRP1); and five are in or near genes involved in neuronal signaling or development. These novel findings point toward multiple genetic factors involved in the development of myopia and suggest that complex interactions between extracellular matrix remodeling, neuronal development, and visual signals from the retina may underlie the development of myopia in humans.

/pdf/genome-wide-analysis-points-to-roles-for-extracellular-5gf1t387ob.pdf

Genome-wide analysis points to roles for extracellular matrix remodeling, the visual cycle, and neuronal development in myopia

Leber congenital amaurosis - a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson Memorial Lecture.

Retinitis 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) genes of unknown function.

Previous studies performed in autosomal recessive retinitis pigmentosa (ARRP) Spanish families have shown that genes coding for recoverin,2 rhodopsin, rod outer segment membrane protein and peripherin/RDS,3 S antigen and the gamma subunit of rod cGMP-phosphodiesterase,4 interstitial retinol binding protein,5 the alpha subunit of rod cGMP-phosphodiesterase and NRL,6 and the retinaldehyde binding protein7 do not play a role in this disorder. However, mutations in the beta subunit of the rod cGMP-phosphodiesterase gene,8–11 in the ATP binding cassette receptor gene,12 in the TULP1 gene,13 in the alpha subunit of the rod cGMP gated channel,14 and in the USH2A gene15 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 …

/pdf/study-of-the-involvement-of-the-rgr-crpb1-and-crb1-genes-in-2b185pcghe.pdf

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

Defects in retinal vitamin A metabolism or in genes expressed in the retinal pigment epithelium (RPE) are related to nonsyndromic retinitis pigmentosa (RP). The RLBP1 gene encodes the cellular retinaldehyde-binding protein which, in the RPE and Muller cells of the retina, is thought to play a role in retinoid metabolism and visual pigment regeneration. We describe a study of the involvement of the RLBP1 gene in 50 autosomal recessive retinitis pigmentosa (ARRP) and four retinitis punctata albescens Spanish families. Cosegregation and homozygosity studies using an intragenic polymorphism and three close markers (D15S116, D15S127, and D15S130) ruled out RLBP1 as the cause of ARRP in 26 pedigrees. In the remaining families, SSCP analysis of the coding region and sequencing of the abnormal migrating bands did not detect any disease-causing mutation. These results indicate that mutations in the RLBP1 gene are not responsible for the ARRP or retinitis punctata albescens in this set of Spanish families. We did, ...

Evaluation of RLBP1 in 50 autosomal recessive retinitis pigmentosa and 4 retinitis punctata albescens Spanish families.

Introduction Multifocal intraocular lens (IOLs) are used to restore vision at different focal distances. The technology of multifocal IOLs is continually advancing. Optical aberrations a property of lenses that causes spreading of light over a region resulting in a blurred or distorted image. This study aims to systematically review investigator measured and patient reported optical aberrations following implantation of multifocal IOLs during phacoemulsification surgery to treat presbyopia in adults. Methods and analysis We will conduct an electronic database search for randomised controlled trials, prospective non-randomised studies, observational studies in Ovid MEDLINE, Ovid EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, Scopus and ClinicalTrials.gov in March 2021. Eligibility criteria will include quantitative articles written in English and containing data on optical aberrations. Two independent reviewers will screen titles and abstracts and extract data from full texts, reporting outcomes according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data extraction of key characteristics will be completed using customised forms. Methodological quality will be assessed using Cochrane Handbook 6.2. Ethics and dissemination Ethics approval is not required for this review, as it will only include published data. Findings will be published in a peer-reviewed journal and disseminated across ophthalmic networks. We anticipate that the findings of this work will be of interest to multiple stakeholders: people who have undergone cataract surgery, eye health professionals, ophthalmic surgeons, device manufacturers and policy-makers. It will also inform researchers to where there are gaps in evidence and identify areas for future research. PROSPERO registration number CRD42021271050.

/pdf/optical-aberrations-following-implantation-of-multifocal-27kb4ur5.pdf

Optical aberrations following implantation of multifocal intraocular lenses: a systematic review and meta-analysis protocol

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Papers

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

Evaluation of RLBP1 in 50 autosomal recessive retinitis pigmentosa and 4 retinitis punctata albescens Spanish families.

Optical aberrations following implantation of multifocal intraocular lenses: a systematic review and meta-analysis protocol