scholarly journals Genetic analysis of 10 pedigrees with inherited retinal degeneration by exome sequencing and phenotype-genotype association

2017 ◽  
Vol 49 (4) ◽  
pp. 216-229 ◽  
Author(s):  
Pooja Biswas ◽  
Jacque L. Duncan ◽  
Bruno Maranhao ◽  
Igor Kozak ◽  
Kari Branham ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Retinal Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Control Sample ◽  
Compound Heterozygous ◽  
Illumina Hiseq ◽  
Retinal Degenerations ◽  
Pathogenic Variants ◽  
Causal Variants

Our purpose was to identify causative mutations and characterize the phenotype associated with the genotype in 10 unrelated families with autosomal recessive retinal degeneration. Ophthalmic evaluation and DNA isolation were carried out in 10 pedigrees with inherited retinal degenerations (IRD). Exomes of probands from eight pedigrees were captured using Nimblegen V2/V3 or Agilent V5+UTR kits, and sequencing was performed on Illumina HiSeq. The DHDDS gene was screened for mutations in the remaining two pedigrees with Ashkenazi Jewish ancestry. Exome variants were filtered to detect candidate causal variants using exomeSuite software. Segregation and ethnicity-matched control sample analysis were performed by dideoxy sequencing. Retinal histology of a patient with DHDDS mutation was studied by microscopy. Genetic analysis identified six known mutations in ABCA4 (p.Gly1961Glu, p.Ala1773Val, c.5461–10T>C), RPE65 (p.Tyr249Cys, p.Gly484Asp), PDE6B (p.Lys706Ter) and DHDDS (p.Lys42Glu) and ten novel potentially pathogenic variants in CERKL (p.Met323Val fsX20), RPE65 (p.Phe252Ser, Thr454Leu fsX31), ARL6 (p.Arg121His), USH2A (p.Gly3142Ter, p.Cys3294Trp), PDE6B (p.Gln652Ter), and DHDDS (p.Thr206Ala) genes. Among these, variants/mutations in two separate genes were observed to segregate with IRD in two pedigrees. Retinal histopathology of a patient with a DHDDS mutation showed severe degeneration of retinal layers with relative preservation of the retinal pigment epithelium. Analysis of exome variants in ten pedigrees revealed nine novel potential disease-causing variants and nine previously reported homozygous or compound heterozygous mutations in the CERKL, ABCA4, RPE65, ARL6, USH2A, PDE6B, and DHDDS genes. Mutations that could be sufficient to cause pathology were observed in more than one gene in one pedigree.

scholarly journals Current Concepts in the Treatment of Retinitis Pigmentosa

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Maria A. Musarella ◽  
Ian M. MacDonald
Keyword(s):  
Retinitis Pigmentosa ◽  
Retinal Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Clinical Severity ◽  
Retinal Implant ◽  
Retinal Degenerations ◽  
Technological Advances ◽  
Stage Disease ◽  
End Stage

Inherited retinal degenerations, including retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA), affect 1 in 4000 individuals in the general population. A majority of the genes which are mutated in these conditions are expressed in either photoreceptors or the retinal pigment epithelium (RPE). There is considerable variation in the clinical severity of these conditions; the most severe being autosomal recessive LCA, a heterogeneous retinal degenerative disease and the commonest cause of congenital blindness in children. Here, we discuss all the potential treatments that are now available for retinal degeneration. A number of therapeutic avenues are being explored based on our knowledge of the pathophysiology of retinal degeneration derived from research on animal models, including: gene therapy, antiapoptosis agents, neurotrophic factors, and dietary supplementation. Technological advances in retinal implant devices continue to provide the promise of vision for patients with end-stage disease.

scholarly journals Therapeutic adenine base editing corrects nonsense mutation and improves visual function in a mouse model of Leber congenital amaurosis

2021 ◽  
Author(s):  
Dong Hyun Jo ◽  
Hyeon-Ki Jang ◽  
Chang Sik Cho ◽  
Jun Hee Han ◽  
Gahee Ryu ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Nonsense Mutation ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Pigment Epithelial Cells ◽  
Subretinal Space ◽  
Leber Congenital Amaurosis ◽  
Base Editing ◽  
Pathogenic Variants ◽  
Adenine Base

Leber congenital amaurosis (LCA) is an inherited retinal degeneration that causes severe visual dysfunction in children and adolescents. In patients with LCA, pathogenic variants are evident in specific genes, such as RPE65, which are related to the functions of retinal pigment epithelium and photoreceptors. Base editing confers a way to correct pathogenic substitutions without double-stranded breaks in contrast to the original Cas9. In this study, we prepared dual adeno-associated virus vectors containing the split adenine base editors with trans-splicing intein (AAV-ABE) for in vivo adenine base editing in retinal degeneration 12 (rd12) mice, an animal model of LCA, which possess a nonsense mutation of C to T transition in the Rpe65 gene (p.R44X). AAV-ABE induced an A to G transition in retinal pigment epithelial cells of rd12 mice when injected into the subretinal space. The on-target editing was sufficient to recover wild-type mRNA, RPE65 protein, and light-induced electrical responses of retinal tissues. We suggest adenine base editing to correct pathogenic variants in the treatment of LCA.

scholarly journals Potential Treatment of Retinal Diseases with Iron Chelators

2018 ◽  
Vol 11 (4) ◽  
pp. 112 ◽  
Author(s):  
Wanting Shu ◽  
Joshua Dunaief
Keyword(s):  
Retinal Degeneration ◽  
Therapeutic Potential ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
The Body ◽  
Age Related Macular Degeneration ◽  
Hereditary Diseases ◽  
Iron Chelators ◽  
Excess Iron ◽  
Age Related

Iron is essential for life, while excess iron can be toxic. Iron generates hydroxyl radical, which is the most reactive free radical, causing oxidative stress. Since iron is absorbed through the diet but not excreted from the body, it accumulates with age in tissues, including the retina, consequently leading to age-related toxicity. This accumulation is further promoted by inflammation. Hereditary diseases such as aceruloplasminemia, Friedreich’s ataxia, pantothenate kinase-associated neurodegeneration, and posterior column ataxia with retinitis pigmentosa involve retinal degeneration associated with iron dysregulation. In addition to hereditary causes, dietary or parenteral iron supplementation has been recently reported to elevate iron levels in the retinal pigment epithelium (RPE) and promote retinal degeneration. Ocular siderosis from intraocular foreign bodies or subretinal hemorrhage can also lead to retinopathy. Evidence from mice and humans suggests that iron toxicity may contribute to age-related macular degeneration pathogenesis. Iron chelators can protect photoreceptors and RPE in various mouse models. The therapeutic potential for iron chelators is under investigation.

scholarly journals Early onset non-syndromic retinal degeneration due to variants in INPP5E: phenotypic expansion of the ciliary gene previously associated with Joubert syndrome

2020 ◽  
Author(s):  
Riccardo Sangermano ◽  
Iris Deitch ◽  
Virginie G Peter ◽  
Rola Ba-Abbad ◽  
Emily M Place ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Early Onset ◽  
Joubert Syndrome ◽  
Phenotypic Correlation ◽  
Cone Dystrophy ◽  
Genetic Modifiers ◽  
Retinal Degenerations ◽  
Pathogenic Variants ◽  
Systemic Disorder ◽  
The Impact

Purpose: Pathogenic variants in INPP5E cause Joubert syndrome, a systemic disorder that can manifest with retinal degeneration among other clinical features. We aimed to evaluate the role of INPP5E variants in non-syndromic inherited retinal degenerations (IRDs) of varying severity. Methods: Targeted or genome sequencing were performed in 12 unrelated non-syndromic IRD families from multiple research hospitals. Detailed clinical examination was conducted in all probands. The impact of new likely pathogenic variants was modeled on a tertiary INPP5E protein structure and all the new and published variants were analyzed for their deleteriousness and phenotypic correlation. Results: Fourteen INPP5E rare alleles were detected, 12 of which were novel. Retinal degeneration in all 12 probands was clinically distinguishable on the basis of onset and severity into Leber congenital amaurosis (n=4) and a milder, later-onset rod-cone dystrophy (n=8). Two probands showed mild ciliopathy features that resolved in childhood. Analysis of the combined impact of both alleles in syndromic and non-syndromic INPP5E patients did not reveal clear genotype-phenotype correlation, suggesting involvement of genetic modifiers. Conclusions: The study expands the phenotypic spectrum of disorders due to pathogenic variants in INPP5E and describes a new disease association with previously underdiagnosed forms of early-onset non-syndromic IRD.

scholarly journals Quantitative metabolomics of photoreceptor degeneration and the effects of stem cell-derived retinal pigment epithelium transplantation

2016 ◽  
Vol 374 (2079) ◽  
pp. 20150376 ◽  
Author(s):  
Junhua Wang ◽  
Peter D. Westenskow ◽  
Mingliang Fang ◽  
Martin Friedlander ◽  
Gary Siuzdak
Keyword(s):  
Stem Cell ◽  
Retinal Pigment Epithelium ◽  
Retinal Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Photoreceptor Degeneration ◽  
Quantitative Metabolomics ◽  
Fatty Acid Amides ◽  
Age Related

Photoreceptor degeneration is characteristic of vision-threatening diseases including age-related macular degeneration. Photoreceptors are metabolically demanding cells in the retina, but specific details about their metabolic behaviours are unresolved. The quantitative metabolomics of retinal degeneration could provide valuable insights and inform future therapies. Here, we determined the metabolomic ‘fingerprint’ of healthy and dystrophic retinas in rat models using optimized metabolite extraction techniques. A number of classes of metabolites were consistently dysregulated during degeneration: vitamin A analogues, fatty acid amides, long-chain polyunsaturated fatty acids, acyl carnitines and several phospholipid species. For the first time, a distinct temporal trend of several important metabolites including DHA (4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid), all- trans -retinal and its toxic end-product N -retinyl- N -retinylidene-ethanolamine were observed between healthy and dystrophic retinas. In this study, metabolomics was further used to determine the temporal effects of the therapeutic intervention of grafting stem cell-derived retinal pigment epithelium (RPE) in dystrophic retinas, which significantly prevented photoreceptor atrophy in our previous studies. The result revealed that lipid levels such as phosphatidylethanolamine in eyes were restored in those animals receiving the RPE grafts. In conclusion, this study provides insight into the metabolomics of retinal degeneration, and further understanding of the efficacy of RPE transplantation. This article is part of the themed issue ‘Quantitative mass spectrometry’.

scholarly journals Retinal degeneration triggered by inactivation of PTEN in the retinal pigment epithelium

2008 ◽  
Vol 22 (22) ◽  
pp. 3147-3157 ◽  
Author(s):  
J. W. Kim ◽  
K. H. Kang ◽  
P. Burrola ◽  
T. W. Mak ◽  
G. Lemke
Keyword(s):  
Retinal Pigment Epithelium ◽  
Retinal Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment

scholarly journals Pharmacological inhibition of MERTK induces in vivo retinal degeneration: a multimodal imaging ocular safety assessment

2022 ◽  
Author(s):  
Gregory Hamm ◽  
Gareth Maglennon ◽  
Beth Williamson ◽  
Ruth Macdonald ◽  
Ann Doherty ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Cell Model ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Cell ◽  
Knock Out ◽  
Pharmacological Inhibition ◽  
Ocular Safety ◽  
Knock Out Mouse

AbstractThe receptor tyrosine kinase, MERTK, plays an essential role in homeostasis of the retina via efferocytosis of shed outer nuclear segments of photoreceptors. The Royal College of Surgeons rat model of retinal degeneration has been linked to loss-of-function of MERTK, and together with the MERTK knock-out mouse, phenocopy retinitis pigmentosa in humans with MERTK mutations. Given recent efforts and interest in MERTK as a potential immuno-oncology target, development of a strategy to assess ocular safety at an early pre-clinical stage is critical. We have applied a state-of-the-art, multi-modal imaging platform to assess the in vivo effects of pharmacological inhibition of MERTK in mice. This involved the application of mass spectrometry imaging (MSI) to characterize the ocular spatial distribution of our highly selective MERTK inhibitor; AZ14145845, together with histopathology and transmission electron microscopy to characterize pathological and ultra-structural change in response to MERTK inhibition. In addition, we assessed the utility of a human retinal in vitro cell model to identify perturbation of phagocytosis post MERTK inhibition. We identified high localized total compound concentrations in the retinal pigment epithelium (RPE) and retinal lesions following 28 days of treatment with AZ14145845. These lesions were present in 4 of 8 treated animals, and were characterized by a thinning of the outer nuclear layer, loss of photoreceptors (PR) and accumulation of photoreceptor outer segments at the interface of the RPE and PRs. Furthermore, the lesions were very similar to that shown in the RCS rat and MERTK knock-out mouse, suggesting a MERTK-induced mechanism of PR cell death. This was further supported by the observation of reduced phagocytosis in the human retinal cell model following treatment with AZ14145845. Our study provides a viable, translational strategy to investigate the pre-clinical toxicity of MERTK inhibitors but is equally transferrable to novel chemotypes.

scholarly journals Ccr2 suppression by minocycline in Cx3cr1/Ccr2-visualized inherited retinal degeneration

2020 ◽  
Author(s):  
Ryo Terauchi ◽  
Hideo Kohno ◽  
Sumiko Watanabe ◽  
Saburo Saito ◽  
Akira Watanabe ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Expression Pattern ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Rescue Effect ◽  
Ccr2 Expression ◽  
Retinal Inflammation ◽  
Inherited Retinal Degeneration ◽  
Old Mice ◽  
Cx3cr1 Expression

AbstractRetinal inflammation accelerates photoreceptor cell death (PCD) caused by retinal degeneration. Minocycline, a semisynthetic broad-spectrum tetracycline antibiotic, has previously been reported to show PCD rescue effect in retinal degeneration. The purpose of this study was to assess the effect of minocycline on Cx3cr1 and Ccr2 expression in retinal degeneration. Mertk-/-Cx3cr1GFP/+Ccr2RFP/+ mice, which enabled observation of Cx3cr1- and Ccr2-expression pattern in inherited retinal degeneration, were used to test the effect of minocycline. Minocycline was systemically administered to Mertk-/-Cx3cr1GFP/+Ccr2RFP/+ mice. For observing the effect of minocycline on Cx3cr1 and Ccr2 expression, administration was started on 4-week-old mice and continued for 2 weeks. To assess the PCD rescue effect, minocycline was administered to 6-week-old mice for 2 weeks. The expression pattern of Cx3cr1-GFP and Ccr2-RFP were observed on retinal and retinal pigment epithelium (RPE) flat-mounts. The severity of retinal degeneration was assessed on retinal sections. Minocycline administration suppressed Ccr2 expression in Mertk-/-Cx3cr1GFP/+Ccr2RFP/+ mice as observed in retinal and RPE flat-mounts. On the contrary, Cx3cr1 expression was not affected by minocycline administration. Retinal degeneration is ameliorated in minocycline administered Mertk-/-Cx3cr1GFP/+Ccr2RFP/+ mice. In conclusions, Minocycline suppression of Ccr2 expression correlates to amelioration of retinal degeneration.

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