scholarly journals Innate and Autoimmunity in the Pathogenesis of Inherited Retinal Dystrophy

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 630 ◽  
Author(s):  
T. J. Hollingsworth ◽  
Alecia K. Gross
Keyword(s):  
Disease Progression ◽  
Age Of Onset ◽  
Retinal Dystrophy ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Major Player ◽  
Inherited Retinal Dystrophy ◽  
Rate Of Progression ◽  
Immunohistochemical Methods ◽  
Onset Rate

Inherited retinal dystrophies (RDs) are heterogenous in many aspects including genes involved, age of onset, rate of progression, and treatments. While RDs are caused by a plethora of different mutations, all result in the same outcome of blindness. While treatments, both gene therapy-based and drug-based, have been developed to slow or halt disease progression and prevent further blindness, only a small handful of the forms of RDs have treatments available, which are primarily for recessively inherited forms. Using immunohistochemical methods coupled with electroretinography, optical coherence tomography, and fluorescein angiography, we show that in rhodopsin mutant mice, the involvement of both the innate and the autoimmune systems could be a strong contributing factor in disease progression and pathogenesis. Herein, we show that monocytic phagocytosis and inflammatory cytokine release along with protein citrullination, a major player in forms of autoimmunity, work to enhance the progression of RD associated with a rhodopsin mutation.

scholarly journals Carbon Dot Nanoparticles: Exploring the Potential Use for Gene Delivery in Ophthalmic Diseases

Nanomaterials ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 935
Author(s):  
Manas R. Biswal ◽  
Sofia Bhatia
Keyword(s):  
Gene Delivery ◽  
Therapeutic Option ◽  
Retinal Dystrophy ◽  
Retinal Cells ◽  
Adeno Associated Virus ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Efficient Gene ◽  
New Type ◽  
Viral Nanoparticles

Ocular gene therapy offers significant potential for preventing retinal dystrophy in patients with inherited retinal dystrophies (IRD). Adeno-associated virus (AAV) based gene transfer is the most common and successful gene delivery approach to the eye. These days, many studies are using non-viral nanoparticles (NPs) as an alternative therapeutic option because of their unique properties and biocompatibility. Here, we discuss the potential of carbon dots (CDs), a new type of nanocarrier for gene delivery to the retinal cells. The unique physicochemical properties of CDs (such as optical, electronic, and catalytic) make them suitable for biosensing, imaging, drug, and gene delivery applications. Efficient gene delivery to the retinal cells using CDs depends on various factors, such as photoluminescence, quantum yield, biocompatibility, size, and shape. In this review, we focused on different approaches used to synthesize CDs, classify CDs, various pathways for the intake of gene-loaded carbon nanoparticles inside the cell, and multiple studies that worked on transferring nucleic acid in the eye using CDs.

scholarly journals Genotype Profile of Global EYS-Associated Inherited Retinal Dystrophy and Clinical Findings in a Large Chinese Cohort

2021 ◽  
Vol 9 ◽  
Author(s):  
Ke Xu ◽  
De-Fu Chen ◽  
Haoyu Chang ◽  
Ren-Juan Shen ◽  
Hua Gao ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Age Of Onset ◽  
Retinal Dystrophy ◽  
Clinical Findings ◽  
Pcr Analysis ◽  
Real Time Quantitative Pcr ◽  
Inherited Retinal Dystrophy ◽  
Chinese Cohort ◽  
Beijing Institute ◽  
Mutation Spectra

PurposeThe aim of this study was to probe the global profile of the EYS-associated genotype-phenotype trait in the worldwide reported IRD cases and to build a model for predicting disease progression as a reference for clinical consultation.MethodsThis retrospective study of 420 well-documented IRD cases with mutations in the EYS gene included 39 patients from a genotype-phenotype study of inherited retinal dystrophy (IRD) conducted at the Beijing Institute of Ophthalmology and 381 cases retrieved from global reports. All patients underwent ophthalmic evaluation. Mutations were revealed using next-generation sequencing, followed by Sanger DNA sequencing and real-time quantitative PCR analysis. Multiple regression models and statistical analysis were used to assess the genotype and phenotype characteristics and traits in this large cohort.ResultsA total of 420 well-defined patients with 841 identified mutations in the EYS gene were successfully obtained. The most common pathogenic variant was a frameshift c.4957dupA (p.S1653Kfs∗2) in exon 26, with an allele frequency of 12.7% (107/841), followed by c.8805C > A (p.Y2935X) in exon 43, with an allele frequency of 5.9% (50/841). Two new hot spots were identified in the Chinese cohort, c.1750G > T (p.E584X) and c.7492G > C (p.A2498P). Several EYS mutation types were identified, with CNV being relatively common. The mean age of onset was 20.54 ± 11.33 (4–46) years. Clinical examinations revealed a typical progression of RPE atrophy from the peripheral area to the macula.ConclusionThis large global cohort of 420 IRD cases, with 262 distinct variants, identified genotype-phenotype correlations and mutation spectra with hotspots in the EYS gene.

scholarly journals Comparative Analysis of Functional and Structural Decline in Retinitis Pigmentosas

2020 ◽  
Vol 21 (8) ◽  
pp. 2730
Author(s):  
Thiago Cabral ◽  
Jose Ronaldo Lima de Carvalho ◽  
Joonpyo Kim ◽  
Jin Kyun Oh ◽  
Sarah R. Levi ◽  
...  
Keyword(s):  
Disease Progression ◽  
Imaging Techniques ◽  
Structural Parameters ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Flicker Erg ◽  
Ring Diameter ◽  
Width Measurements ◽  
One Year ◽  
Sd Oct

Retinitis pigmentosa (RP) is a category of inherited retinal dystrophies that is best prognosticated using electroretinography (ERG). In this retrospective cohort study of 25 patients with RP, we evaluated the correlation between 30 Hz flicker ERG and structural parameters in the retina. Internationally standardized 30 Hz flicker ERG recordings, short-wavelength autofluorescence (SW-AF), and spectral domain–optical coherence tomography (SD-OCT) were acquired at two visits at least one year apart. Vertical and horizontal hyperautofluorescent ring diameter measurements with SW-AF, as well as ellipsoid zone (EZ) line width measurements with SD-OCT, were used as structural parameters of disease progression. The 30 Hz flicker ERG amplitude decreased by 2.2 ± 0.8 µV/year (p = 0.011), while implicit times remained unchanged. For SD-OCT, the EZ line decreased by 204.1 ± 34.7 µm/year (p < 0.001). Horizontal and vertical hyperautofluorescent ring diameters decreased by 161.9 ± 25.6 µm/year and 146.9 ± 34.6 µm/year, respectively (p = 0.001), with SW-AF. A correlation was found between the progression rates of the 30 Hz flicker amplitude recorded with Burian–Allen electrodes and both the horizontal ring diameter (p = 0.020) and EZ line (p = 0.044). SW-AF and SD-OCT, two readily available imaging techniques, may be used to prognosticate disease progression because of the reliability of their measurements and correlation with functional outcome.

scholarly journals Pathogenicity Reclassification of RPE65 Missense Variants Related to Leber Congenital Amaurosis and Early-Onset Retinal Dystrophy

Genes ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 24 ◽  
Author(s):  
Fabiana Motta ◽  
Renan Martin ◽  
Fernanda Porto ◽  
Elizabeth Wohler ◽  
Rosane Resende ◽  
...  
Keyword(s):  
Molecular Diagnosis ◽  
Early Onset ◽  
Retinal Dystrophy ◽  
Low Frequency ◽  
Sequencing Data ◽  
Leber Congenital Amaurosis ◽  
Missense Variants ◽  
Inherited Retinal Dystrophies ◽  
Inherited Retinal Dystrophy ◽  
Uncertain Significance

A challenge in molecular diagnosis and genetic counseling is the interpretation of variants of uncertain significance. Proper pathogenicity classification of new variants is important for the conclusion of molecular diagnosis and the medical management of patient treatments. The purpose of this study was to reclassify two RPE65 missense variants, c.247T>C (p.Phe83Leu) and c.560G>A (p.Gly187Glu), found in Brazilian families. To achieve this aim, we reviewed the sequencing data of a 224-gene retinopathy panel from 556 patients (513 families) with inherited retinal dystrophies. Five patients with p.Phe83Leu and seven with p.Gly187Glu were selected and their families investigated. To comprehend the pathogenicity of these variants, we evaluated them based on the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) classification guidelines. Initially, these RPE65 variants met only three pathogenic criteria: (i) absence or low frequency in the population, (ii) several missense pathogenic RPE65 variants, and (iii) 15 out of 16 lines of computational evidence supporting them as damaging, which together allowed the variants to be classified as uncertain significance. Two other pieces of evidence were accepted after further analysis of these Brazilian families: (i) p.Phe83Leu and p.Gly187Glu segregate with childhood retinal dystrophy within families, and (ii) their prevalence in Leber congenital amaurosis (LCA)/early-onset retinal dystrophy (EORD) patients can be considered higher than in other inherited retinal dystrophy patients. Therefore, these variants can now be classified as likely pathogenic according to ACMG/AMP classification guidelines.

scholarly journals Genetic and Phenotypic Landscape of PRPH2-Associated Retinal Dystrophy in Japan

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1817
Author(s):  
Akio Oishi ◽  
Kaoru Fujinami ◽  
Go Mawatari ◽  
Nobuhisa Naoi ◽  
Yasuhiro Ikeda ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Age Of Onset ◽  
Phenotypic Variability ◽  
Retinal Dystrophy ◽  
Japanese Patients ◽  
Macular Dystrophy ◽  
Hand Motion ◽  
Pathogenic Variants ◽  
Inherited Retinal Dystrophy ◽  
Asian Cohort

Peripherin-2 (PRPH2) is one of the causative genes of inherited retinal dystrophy. While the gene is relatively common in Caucasians, reports from Asian ethnicities are limited. In the present study, we report 40 Japanese patients from 30 families with PRPH2-associated retinal dystrophy. We identified 17 distinct pathogenic or likely pathogenic variants using next-generation sequencing. Variants p.R142W and p.V200E were relatively common in the cohort. The age of onset was generally in the 40’s; however, some patients had earlier onset (age: 5 years). Visual acuity of the patients ranged from hand motion to 1.5 (Snellen equivalent 20/13). The patients showed variable phenotypes such as retinitis pigmentosa, cone-rod dystrophy, and macular dystrophy. Additionally, intrafamilial phenotypic variability was observed. Choroidal neovascularization was observed in three eyes of two patients with retinitis pigmentosa. The results demonstrate the genotypic and phenotypic variations of the disease in the Asian cohort.

scholarly journals Retinitis Pigmentosa withEYSMutations Is the Most Prevalent Inherited Retinal Dystrophy in Japanese Populations

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Yuuki Arai ◽  
Akiko Maeda ◽  
Yasuhiko Hirami ◽  
Chie Ishigami ◽  
Shinji Kosugi ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Direct Sequencing ◽  
Retinal Dystrophy ◽  
In Silico Analysis ◽  
Japanese Patients ◽  
Sequence Variants ◽  
Stargardt Disease ◽  
Identification Rate ◽  
Inherited Retinal Dystrophies ◽  
Inherited Retinal Dystrophy

The aim of this study was to gain information about disease prevalence and to identify the responsible genes for inherited retinal dystrophies (IRD) in Japanese populations. Clinical and molecular evaluations were performed on 349 patients with IRD. For segregation analyses, 63 of their family members were employed. Bioinformatics data from 1,208 Japanese individuals were used as controls. Molecular diagnosis was obtained by direct sequencing in a stepwise fashion utilizing one or two panels of 15 and 27 genes for retinitis pigmentosa patients. If a specific clinical diagnosis was suspected, direct sequencing of disease-specific genes, that is,ABCA4for Stargardt disease, was conducted. Limited availability of intrafamily information and decreasing family size hampered identifying inherited patterns. Differential disease profiles with lower prevalence of Stargardt disease from European and North American populations were obtained. We found 205 sequence variants in 159 of 349 probands with an identification rate of 45.6%. This study found 43 novel sequence variants. In silico analysis suggests that 20 of 25 novel missense variants are pathogenic.EYSmutations had the highest prevalence at 23.5%. c.4957_4958insA and c.8868C>A were the two majorEYSmutations identified in this cohort.EYSmutations are the most prevalent among Japanese patients with IRD.

scholarly journals NRL S50T mutation and the importance of ‘founder effects’ in inherited retinal dystrophies

2000 ◽  
Vol 8 (10) ◽  
pp. 783-787 ◽  
Author(s):  
David AR Bessant ◽  
Annette M Payne ◽  
Catherine Plant ◽  
Alan C Bird ◽  
Anand Swaroop ◽  
...  
Keyword(s):  
Founder Effects ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies

scholarly journals Bestrophinopathies: perspectives on clinical disease, Bestrophin-1 function and developing therapies

2021 ◽  
Vol 13 ◽  
pp. 251584142199719
Author(s):  
Simranjeet Singh Grewal ◽  
Joseph J. Smith ◽  
Amanda-Jayne F. Carr
Keyword(s):  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Induced Pluripotent Stem Cell ◽  
Underlying Disease ◽  
Incomplete Penetrance ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
High Acuity ◽  
Induced Pluripotent

Bestrophinopathies are a group of clinically distinct inherited retinal dystrophies that typically affect the macular region, an area synonymous with central high acuity vision. This spectrum of disorders is caused by mutations in bestrophin1 ( BEST1), a protein thought to act as a Ca2+-activated Cl- channel in the retinal pigment epithelium (RPE) of the eye. Although bestrophinopathies are rare, over 250 individual pathological mutations have been identified in the BEST1 gene, with many reported to have various clinical expressivity and incomplete penetrance. With no current clinical treatments available for patients with bestrophinopathies, understanding the role of BEST1 in cells and the pathological pathways underlying disease has become a priority. Induced pluripotent stem cell (iPSC) technology is helping to uncover disease mechanisms and develop treatments for RPE diseases, like bestrophinopathies. Here, we provide a comprehensive review of the pathophysiology of bestrophinopathies and highlight how patient-derived iPSC-RPE are being used to test new genomic therapies in vitro.

scholarly journals Nutraceutical Supplementation Ameliorates Visual Function, Retinal Degeneration, and Redox Status in rd10 Mice

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1033
Author(s):  
Lorena Olivares-González ◽  
Sheyla Velasco ◽  
Isabel Campillo ◽  
David Salom ◽  
Emilio González-García ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Retinal Degeneration ◽  
Antioxidant Properties ◽  
Photoreceptor Cells ◽  
Redox Status ◽  
Inherited Retinal Dystrophies ◽  
Stress Markers ◽  
Retinal Dystrophies ◽  
Progressive Degeneration ◽  
Light Stimuli

Background: Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by progressive degeneration of photoreceptor cells. Ocular redox status is altered in RP suggesting oxidative stress could contribute to their progression. In this study, we investigated the effect of a mixture of nutraceuticals with antioxidant properties (NUT) on retinal degeneration in rd10 mice, a model of RP. Methods: NUT was orally administered to rd10 mice from postnatal day (PD) 9 to PD18. At PD18 retinal function and morphology were examined by electroretinography (ERG) and histology including TUNEL assay, immunolabeling of microglia, Müller cells, and poly ADP ribose polymers. Retinal redox status was determined by measuring the activity of antioxidant enzymes and some oxidative stress markers. Gene expression of the cytokines IL-6, TNFα, and IL-1β was assessed by real-time PCR. Results: NUT treatment delayed the loss of photoreceptors in rd10 mice partially preserving their electrical responses to light stimuli. Moreover, it ameliorated redox status and reduced inflammation including microglia activation, upregulation of cytokines, reactive gliosis, and PARP overactivation. Conclusions: NUT ameliorated retinal functionality and morphology at early stages of RP in rd10 mice. This formulation could be useful as a neuroprotective approach for patients with RP in the future.

Na-K-activated adenosinetriphosphatase in retinae of rats with and without inherited retinal dystrophy

1970 ◽  
Vol 10 (5) ◽  
pp. 435-438 ◽  
Author(s):  
F.J.M. Daemen ◽  
J.J.H.H.M. de Pont ◽  
F. Lion ◽  
S.L. Bonting
Keyword(s):  
Retinal Dystrophy ◽  
Inherited Retinal Dystrophy
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