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Characterization of RPGR Variants and Their Role in Inherited Retinal DegenerationWright, Rachel 2011 August 1900 (has links)
Retinitis Pigmentosa (RP) refers to a group of inherited retinal dystrophies resulting from progressive photoreceptor degeneration and accumulation of intra-retinal pigment-like deposits. X-linked forms of RP are frequently caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. The RPGR transcript undergoes complex alternative splicing to express both constitutive (RPGR^ex1-19) and RPGR^ORF15 variants. Although RPGR is thought to play a role in ciliary function, little is known about the physiological significance of expressing two distinct groups of variants. This study compares Rpgr^ex1-19 and Rpgr^ORF15 expression in developing photoreceptors using immunoblot analysis and immunohistochemistry, assesses ciliary affinity in adult photoreceptors by protein fractionation, examines Rpgr function in transgenic mouse models and identifies a novel Rpgr^ORF15 binding partner using a yeast two-hybrid screen.
Our data reveal that Rpgr expression undergoes dynamic temporal regulation during retinal development and indicates variability in ciliary localization of Rpgr variants in adult photoreceptors. Utilization of distinct Rpgr variants during stages of photoreceptor development suggests independent roles. Further examination of Rpgr function using transgenic mouse models over-expressing either the Rpgr^ex1-19 or Rpgr^ORF15 variant reveals that despite normal ciliary localization, an excess of RPGR^ex1-19 results in atypical accumulation of Rpgr in photoreceptor outer segments, abnormal photoreceptor morphology and severe retinal degeneration. The data indicate that the constitutive variant cannot substitute for Rpgr function in photoreceptors and suggest that proper maintenance of the Rpgr isoform ratio is critical to photoreceptor viability.
Using mouse retinal cDNA in a yeast two-hybrid screen with the C-terminus of the Rpgr^ORF15 variant, we identified a novel variant of whirlin as an interacting partner. Mutations in whirlin result in Usher syndrome, a disorder characterized by hearing loss and RP. RT-PCR and immunoblot analysis were used to confirm the presence of selected candidate partners in the retina and interaction was confirmed by pull-down assays and co-immunoprecipitation from retinal homogenate. Immunohistochemistry showed co-localization of RPGR and whirlin within photoreceptors and identified isoform specific localization of whirlin. These findings indicate that whirlin binds Rpgr^ORF15 and that this novel isoform may be required for photoreceptor function, thus providing a potential mechanism for the RP phenotype observed in Usher syndrome.
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Mellan Hopp och FörtvivlanHansson, Fredrik, Campos, Kim January 2007 (has links)
Detta är en studie om hur det är att studera på Högskolan i Halmstad när man har någon form av funktionsnedsättning. Vi har i denna studie tittat på hur deras funktionsnedsättning har påverkat deras liv allt ifrån när de fick sina diagnoser tills det att de började studera. Vi har även velat få fram hur deras funktionsnedsättning har påverkat deras studier i den bemärkelse att dem har fått stöd och olika hjälpmedel för att klara av dessa. I denna studie så har vi också tagit reda på hur mycket tid och energi som studenterna får lägga ner på sitt skolarbete, men också hur allt detta har påverkat deras sociala tillvaro i och utanför skolan. Vi har även försökt ta fasta på vad studenterna upplever som problematiskt under sin studietid, och tittat på om deras funktionsnedsättning varit en orsakande faktor i detta.
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INVESTIGATION INTO THE REGULATION OF INOSINE MONOPHOSPHATE DEHYDROGENASE (IMPDH)Elaine Thomas Unknown Date (has links)
Inosine monophosphate dehydrogenase (IMPDH) catalyses the key step in de novo guanine nucleotide biosynthesis at the branch point of GTP and ATP production. Mammals have two ubiquitous, catalytically indistinguishable isoforms, IMPDH type I and type II, and these are considered functionally interchangeable. Each contains a Bateman domain known to serve as energy-sensing / allosteric regulatory modules in a range of unrelated proteins. Mutations in the Bateman domain of type I, which do not affect catalytic activity, cause the retina-degenerative disease, retinitis pigmentosa (RP). The central hypothesis of this thesis is that IMPDH is regulated. In particular, that regulation occurs in an isoform specific manner and that mutations causal to RP affect enzyme regulation. Here we have visualised, including in real-time, the redistribution or clustering of IMPDH into linear macrostructures in a time-dependent manner which appeared to be intimately associated with changes in intracellular nucleotide levels. Data presented suggest the significance of IMPDH clustering is unlikely to be associated with substrate channelling, via interaction with other proteins in the de novo biosynthesis pathway, or enhanced protein stability. Although both isoforms responded similarly to fluctuations in intracellular nucleotide levels, type I had a higher propensity to spontaneously cluster into macrostructures compared to type II. This propensity to cluster was found to be conferred by the N-terminal 244 amino acids, which includes the Bateman domain, using a series of type I / type II chimera proteins. A comparative and novel approach revealed isoform-specific purine nucleotide binding characteristics. Type I bound ATP and type II bound AMP, via a mechanism involving the Bateman domain, resulting in conformational changes in IMPDH. This nucleotide binding was not associated with allosteric activation of IMPDH catalytic activity. The RP-causing mutation, R224P, abolished ATP binding and this correlated with an altered propensity to cluster. Collectively these data (i) show IMPDH distribution is regulated by the intracellular environment (ii) demonstrate that the IMPDH isoforms are modulated in a differential manner by AMP and ATP by a mechanism involving the Bateman domain, (iii) indicate communication between the Bateman domain and the active site and (iv) demonstrate that a RP-causing mutation compromises such regulation. From a broader perspective, this work raises the possibility that the nucleotide sensing properties of the Bateman domain in IMPDH serve to regulate IMPDH and co-ordinate nucleotide homeostasis, thereby giving rise to cellular plasticity in an isoform-specific manner to meet the requirements of the cellular environment.
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Verwantschap en erfelijkheid bij doofstomheid en retinitis pigmentosa ...Wilde, Pieter Adrianus de. January 1919 (has links)
Proefschrift - Amsterdam. / "Geraadpleegde literatuur": p. [90]-91.
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Perception of genetic testing among patients with inherited retinal disease: Benefits and challenges in a Japanese population / 日本の遺伝性網膜変性疾患患者における遺伝子診断の認識:ベネフィットと課題Inaba, Akira 23 May 2022 (has links)
京都大学 / 新制・課程博士 / 博士(医学) / 甲第24087号 / 医博第4863号 / 新制||医||1059(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 近藤 尚己, 教授 山本 洋介, 教授 辻川 明孝 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM
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The Effect of Cell Type on the Efficacy of CMV Antiviral DrugsMeza, Benjamin 01 January 2008 (has links)
Until recently, all in vitro drug susceptibility assays of cytomegalovirus (CMV) were performed in clinically irrelevant fibroblast cells. This study sought to test if drug susceptibility was affected by cell type. MRC-5 embryonic lung fibroblasts and ARPE-19 retinal pigmented epithelial cells were infected with BADrUL131-Y4 epithelial/fibroblast tropic virus under serial concentrations of ganciclovir (GCV) or maribavir (MBV). Virus was quantified using plaque reduction, GFP fluorescence, and yield reduction. Both drugs performed less efficiently in ARPE-19 cells. A cell type effect was observed for both plaque reduction and yield reduction assays with implications for the treatment of CMV retinitis as well as other manifestations of CMV Disease that involve non-fibroblast cell types.
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Funkční analýza mutací hPrp8 spojených s onemocněním retinitis pigmentosa. / Functional analysis of hPrp8 mutations linked to retinitis pigmentosa.Matějů, Daniel January 2013 (has links)
hPrp8 is an essential pre-mRNA splicing factor. This highly conserved protein is a component of the U5 small ribonucleoprotein particle (U5 snRNP), which constitutes one of the building blocks of the spliceosome. hPrp8 acts as a key regulator of spliceosome activation and interacts directly with U5 snRNA and with the regions of pre-mRNA that are involved in the transesterification reactions during splicing. Mutations in hPrp8 have been shown to cause an autosomal dominant form of retinitis pigmentosa (RP), an inherited disease leading to progressive degeneration of retina. In this study, we analyzed the effects of the RP-associated mutations on the function of hPrp8. Using BAC recombineering, we created mutant variants of hPrp8-GFP construct and we generated stable cell lines expressing the recombinant proteins. The mutant proteins were expressed and localized to the nucleus. However, one of the missense mutations affected the localization and stability of hPrp8. Further experiments suggested that RP-associated mutations affect the ability of hPrp8 to interact with other components of the U5 snRNP and with pre-mRNA. We further studied the biogenesis of U5 snRNP. We depleted hPrp8 by siRNA to interfere with U5 snRNP assembly and we observed that the incompletely assembled U5 snRNPs accumulate in...
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Manifestações clínicas e complicações associadas à toxoplasmose ocular / Clinical manifestations and complications associated with ocular toxoplasmosisArruda, Sigrid Lorena Batista 08 May 2018 (has links)
Neste estudo, foram descritos os aspectos clínicos e resultados visuais em indivíduos com evidência sorológica e sinais clínicos de toxoplasmose ocular. Os sujeitos foram examinados com lâmpada de fenda, exame de oftalmoscopia indireta, tendo registros fotográficos com retinografia e tomografia de coerência óptica. Duzentos e sessenta e sete participantes foram incluídos no estudo (n = 350 olhos). A forma de toxoplasmose ocular foi considerada primária em 52 indivíduos (19,5%), recorrente ativa em 89 (33,3%) e inativa em 126 (47,2%). A maioria dos olhos apresentou uma lesão (n=169; 48,3%), enquanto que 149 olhos (42,6%) apresentaram duas a quatro lesões e 32, cinco ou mais lesões (9,1%). As lesões centrais estiveram presentes em 127 olhos (36,3%), periféricas em 178 (50,9%), enquanto que lesões centrais e periféricas em 45 (12,6%). A maioria dos indivíduos apresentou sorologia para toxoplasma gondii (T. gondii) IgG + IgM- (n=245; 91,8%), enquanto que apenas 22 (8,2%) foram T. gondii IgG + IgM +. Do total de olhos afetados em que a acuidade visual foi medida (n=314), a maioria (n=160; 50,9%) apresentou melhor acuidade visual corrigida final >20/40, e 25,8% (n=81) foram considerados cegos (<20/400). Lesões múltiplas, de localização central e com tamanho maior que um diâmetro de disco óptico foram consideradas fator de risco para pior prognóstico visual. A membrana epirretiniana (n=21; 7,1%) e opacidade vítrea (n=20; 6,8%) foram as principais causas de complicações observadas. A taxa de incidência de complicações foi de 0,41 complicações/ano, e foram verificadas 0,13 reativações/ano. O estudo demonstrou altas taxas de déficit visual, devendo ser realizados novos estudos para o desenvolvimento de novas modalidades terapêuticas para diminuir o impacto da doença como causa de cegueira e deficiência visual. / In this study, we describe the clinical aspects clinical aspects and visual outcomes in individuals with serological evidence and clinical signs of ocular toxoplasmosis. The subjects were examined with a slit lamp, indirect ophthalmoscopy examination, having photographic records with retinography and optical coherence tomography. Two hundred and sixty -seven subjects were included in the study (n=350 eyes). The form of ocular toxoplasmosis was considered primary active in 52 subjects (19.5%), recurrent active in 89 subjects (33.3%) and inactive in 126 (47.2%). Most eyes presented only one lesion (n=169; 48.3%), whereas 149 individuals (42,6%) had 2-4 lesions, and 32 had five or more lesions (9.1%). Central lesions only were present in 127 eyes (36,3%), peripheral in 178 (50,9%%), while concomitant central and peripheral were present in 45 (12.6%). Most subjects had T. gondii IgG+ IgMserology (n=245; 91.8%), whereas only 22 (8,2%) were T. gondii IgG+ IgM+. From the total of affected eyes which visual acuity was measured (n=314), most (n=160; 50,9%) had better final corrected visual acuity> 20/40 and 25.8% (n = 81) were considered blind (<20/400). Multiple, centrally located lesions of greater size than an optic disc diameter were considered risk factor for a worse visual prognosis. The epiretinal membrane (n=21; 7.1%) and vitreous opacity (n=20; 6.8%) were the main causes of complications seen. The incidence rate of complications was 0,41 complications/year, and it was verified 0,13 reactivations/year. The study demonstrated a high rate of visual impairment, and studies for the development of novel therapeutic modalities should be performed to reduce the impact of the disease as a cause of blindness and visual impairment.
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Em busca de novos métodos de tratamento para a retinose pigmentar causada por mutações na rodopsina. / Finding new approaches to treat retinitis pigmentosa caused by mutations in the photoreceptor rhodopsin.Balen, Fernanda 05 July 2012 (has links)
Retinose Pigmentar (RP) é uma doença hereditária que conduz progressivamente à cegueira. Mais de 150 mutações da rodopsina associadas à RP foram descritas, e causam a alteração da sua conformação. Esta tese testou a hipótese de que pequenas moléculas auxiliam na formação da rodopsina e/ou reduzem a morte dos fotorreceptores. As mutações da RP, N15S e P23H, revelaram diferenças quanto às características e gravidade devido à má-formação das proteínas mutantes. Ligação de pequenas moléculas (retinóides, íons metálicos, clorofilas e antocianinas) à rodopsina foi demonstrada in vitro. O derivado da clorofila, Ce6, mostrou-se mais efetivo, conferindo maior estabilidade e foi então testado em ratos submetidos à degeneração por luz ou em modelos de RP (P23H e S334ter). Observou-se uma proteção contra a degeneração por luz e uma significante diminuição da degeneração no P23H. Em contraste, Ce6 causou um aumento na degeneração dos fotorreceptores do S334ter. Finalmente, resultados clínicos, bioquímicos e in vivo foram comparados e mostraram estar altamente relacionados. / Retinitis Pigmentosa (RP) is an inherited disease that progressively leads to blindness. More than 150 mutations associated with RP are known in rhodopsin, causing its misfolding. This thesis tested the hypothesis that small molecules can rescue folded rhodopsin and/or reduce photoreceptor cell death. RP mutations, N15S and P23H, revealed differences in characteristics and severity of misfolding of the mutant proteins. Binding of small molecule classes (retinals, metal ions, chlorophylls and anthocyanins) to rhodopsin was demonstrated in vitro. The chlorophyll derivative, Ce6, was most effective in conferring stability and therefore tested in rats subjected to light-damage and RP rat models, P23H and S334ter. Protection against the light-induced retinal degeneration and more importantly a significant slowing of the photoreceptor degeneration rate in the P23H rat were observed. In contrast, Ce6 increased photoreceptor degeneration in the S334ter rat. Finally, clinical, biochemical and in vivo rat data were compared and it was found to be highly correlated.
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Molecular mechanisms underlying Retinitis pigmentosa type 2Lyraki, Rodanthi January 2018 (has links)
The term 'Retinitis pigmentosa' (RP) represents a group of inherited, late-onset diseases characterised by progressive retinal degeneration due to photoreceptor death. Mutations in the RP2 gene are found in 7-18% of patients with X-linked RP, one of the most severe forms. The RP2 gene product is a membrane-associated protein which encompasses two distinct domains. The N-terminal domain is well characterised as possessing GTPase-activating protein (GAP) activity towards the small GTPase ARL3 and thus regulate the transport of lipid-modified proteins within the photoreceptor cell. However, it is not known if the loss of this particular function of RP2 is the sole reason that causes the disease, while the role of the protein's C-terminus remains unknown. This thesis focuses on the characterisation of two novel protein-protein interactions of RP2 with the aim to investigate novel roles of the protein. Firstly, evidence is provided that a highly-conserved cluster of RP2 residues that span both the N- and C-terminus participate in direct interaction with Osteoclast-stimulating factor 1 (OSTF1). Two hypotheses are explored about the potential role of the complex in SRC-mediated RP2 phosphorylation and the regulation of cell motility. Secondly, the catalytic subunit of DNA-dependent protein kinase (DNA PK) is identified as a novel interaction partner of RP2 in cultured cells. The two proteins are shown to co-localise in the nuclear and membrane compartments of a retinal-derived cell line and might engage in a kinase-substrate relationship. So far, no evidence was found that RP2 participates in the canonical function of DNA PK which is the regulation of DNA double-stranded breaks. Finally, the CRISPR/Cas9 genome editing method was applied on zebrafish embryos to generate a novel vertebrate animal model for the loss of RP2 function. One out of three different zebrafish lines with rp2 mutations was shown by histology to have mild late-onset thinning of the photoreceptor outer segments. The present thesis reports previously unexplored aspects of RP2's function and will, therefore, contribute to understanding the molecular mechanisms that underlie RP. Moreover, this thesis will contribute to the discussion about the usefulness of zebrafish as an RP model.
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