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https://www.readbyqxmd.com/read/28395299/multimodal-fundus-imaging-of-sodium-iodate-treated-mice-informs-rpe-susceptibility-and-origins-of-increased-fundus-autofluorescence
#1
Jin Zhao, Hye Jin Kim, Janet R Sparrow
Purpose: By multimodal imaging, and the use of mouse and in vitro models, we have addressed changes in fundus autofluorescence (488 and 790 nm) and observed interactions between the photooxidative stress imposed by RPE bisretinoid lipofuscin and the oxidative impact of systemic sodium iodate (NaIO3). Methods: Abca4-/-, wild-type, and Rpe65rd12 mice were given systemic injections of NaIO3 (30 mg/kg). Analysis included noninvasive imaging of fundus autofluorescence (short-wavelength [SW-AF]; near-infrared excitation [NIR-AF]), quantitative fundus AF (qAF; 488 nm); light microscopy, RPE flat-mounts and measurements of outer nuclear layer (ONL) thickness...
April 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28370415/top2b-is-involved-in-the-formation-of-outer-segment-and-synapse-during-late-stage-photoreceptor-differentiation-by-controlling-key-genes-of-photoreceptor-transcriptional-regulatory-network
#2
Ying Li, Hailing Hao, Mavis R Swerdel, Hyeon-Yeol Cho, Ki-Bum Lee, Ronald P Hart, Yi Lisa Lyu, Li Cai
Topoisomerase II beta (Top2b) is an enzyme that alters the topologic states of DNA during transcription. Top2b deletion in early retinal progenitor cells causes severe defects in neural differentiation and affects cell survival in all retinal cell types. However, it is unclear whether the observed severe phenotypes are the result of cell-autonomous/primary defects or non-cell-autonomous/secondary defects caused by alterations of other retinal cells. Using photoreceptor cells as a model, we first characterized the phenotypes in Top2b conditional knockout...
March 30, 2017: Journal of Neuroscience Research
https://www.readbyqxmd.com/read/28365912/multimodal-analysis-of-the-preferred-retinal-location-and-the-transition-zone-in-patients-with-stargardt-disease
#3
Tommaso Verdina, Vivienne C Greenstein, Andrea Sodi, Stephen H Tsang, Tomas R Burke, Ilaria Passerini, Rando Allikmets, Gianni Virgili, Gian Maria Cavallini, Stanislao Rizzo
PURPOSE: The purpose of our study was to investigate morpho-functional features of the preferred retinal location (PRL) and the transition zone (TZ) in a series of patients with recessive Stargardt disease (STGD1). METHODS: Fifty-two STGD1 patients with at least one ABCA4 mutation, atrophy of the central macula (MA) and an eccentric PRL were recruited for the study. Microperimetry, fundus autofluorescence (FAF), spectral-domain optical coherence tomography (SD-OCT) were performed...
April 2, 2017: Graefe's Archive for Clinical and Experimental Ophthalmology
https://www.readbyqxmd.com/read/28355279/highly-sensitive-measurements-of-disease-progression-in-rare-disorders-developing-and-validating-a-multimodal-model-of-retinal-degeneration-in-stargardt-disease
#4
Stanley Lambertus, Nathalie M Bax, Ana Fakin, Joannes M M Groenewoud, B Jeroen Klevering, Anthony T Moore, Michel Michaelides, Andrew R Webster, Gert Jan van der Wilt, Carel B Hoyng
BACKGROUND: Each inherited retinal disorder is rare, but together, they affect millions of people worldwide. No treatment is currently available for these blinding diseases, but promising new options-including gene therapy-are emerging. Arguably, the most prevalent retinal dystrophy is Stargardt disease. In each case, the specific combination of ABCA4 variants (> 900 identified to date) and modifying factors is virtually unique. It accounts for the vast phenotypic heterogeneity including variable rates of functional and structural progression, thereby potentially limiting the ability of phase I/II clinical trials to assess efficacy of novel therapies with few patients...
2017: PloS One
https://www.readbyqxmd.com/read/28348233/complement-modulation-in-the-retinal-pigment-epithelium-rescues-photoreceptor-degeneration-in-a-mouse-model-of-stargardt-disease
#5
Tamara L Lenis, Shanta Sarfare, Zhichun Jiang, Marcia B Lloyd, Dean Bok, Roxana A Radu
Recessive Stargardt macular degeneration (STGD1) is caused by mutations in the gene for the ABCA4 transporter in photoreceptor outer segments. STGD1 patients and Abca4(-/-) (STGD1) mice exhibit buildup of bisretinoid-containing lipofuscin pigments in the retinal pigment epithelium (RPE), increased oxidative stress, augmented complement activation and slow degeneration of photoreceptors. A reduction in complement negative regulatory proteins (CRPs), possibly owing to bisretinoid accumulation, may be responsible for the increased complement activation seen on the RPE of STGD1 mice...
April 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28341476/panel-based-clinical-genetic-testing-in-85-children-with-inherited-retinal-disease
#6
Rachel L Taylor, Neil R A Parry, Stephanie J Barton, Christopher Campbell, Claire M Delaney, Jamie M Ellingford, Georgina Hall, Claire Hardcastle, Jiten Morarji, Elisabeth J Nichol, Lindsi C Williams, Sofia Douzgou, Jill Clayton-Smith, Simon C Ramsden, Vinod Sharma, Susmito Biswas, I Chris Lloyd, Jane L Ashworth, Graeme C Black, Panagiotis I Sergouniotis
PURPOSE: To assess the clinical usefulness of genetic testing in a pediatric population with inherited retinal disease (IRD). DESIGN: Single-center retrospective case series. PARTICIPANTS: Eighty-five unrelated children with a diagnosis of isolated or syndromic IRD who were referred for clinical genetic testing between January 2014 and July 2016. METHODS: Participants underwent a detailed ophthalmic examination, accompanied by electrodiagnostic testing (EDT) and dysmorphologic assessment where appropriate...
March 21, 2017: Ophthalmology
https://www.readbyqxmd.com/read/28327576/genotypic-spectrum-and-phenotype-correlations-of-abca4-associated-disease-in-patients-of-south-asian-descent
#7
Winston Lee, Kaspar Schuerch, Jana Zernant, Frederick T Collison, Srilaxmi Bearelly, Gerald A Fishman, Stephen H Tsang, Janet R Sparrow, Rando Allikmets
Variants in the ABCA4 gene are the most common cause of juvenile-onset blindness affecting close to 1 in 10 000 people worldwide. Disease severity varies largely according to genotype, which can be specific to ethnic and racial groups. Here we investigate the spectrum of ABCA4 variation and its phenotypic expression in 38 patients of South Asian descent, notably from India, Pakistan, Bangladesh and Sri Lanka. Sequencing of all exons and flanking intronic sequences of ABCA4 revealed disease-causing variants in all patients: 3 in 2...
March 22, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28302729/phagocytosis-dependent-ketogenesis-in-retinal-pigment-epithelium
#8
Juan Reyes-Reveles, Anuradha Dhingra, Desiree Alexander, Alvina Bragin, Nancy J Philp, Kathleen Boesze-Battaglia
Daily, the retinal pigment epithelium (RPE) ingests a bolus of lipid and protein in the form of phagocytized photoreceptor outer segments (OS). The RPE like the liver expresses enzymes required for fatty acid oxidation (FAO) and ketogenesis. This suggests that these pathways play a role in the disposal of lipids from ingested OS as well as providing a mechanism for recycling metabolic intermediates back to the outer retina. In this study, we examined whether OS phagocytosis was linked to ketogenesis. We found increased levels of β-hydroxy-butyrate (β-HB) in the apical media following ingestion of OS by human fetal RPE and ARPE19 cells cultured on transwell inserts...
March 16, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28290600/possible-protective-role-of-the-abca4-gene-c-1268a-g-missense-variant-in-stargardt-disease-and-syndromic-retinitis-pigmentosa-in-a-sicilian-family-preliminary-data
#9
Rosalia D'Angelo, Luigi Donato, Isabella Venza, Concetta Scimone, Pasquale Aragona, Antonina Sidoti
In the wide horizon of ophthalmologically rare diseases among retinitis pigmentosa forms, Stargardt disease has gradually assumed a significant role due to its heterogeneity. In the present study, we aimed to support one of two opposite hypotheses concerning the causative or protective role of heterozygous c.1268A>G missense variant of the ABCA4 gene in Stargardt disease and in syndromic retinitis pigmentosa. This study was based on a family consisting of three members: proband, age 54, with high myopia, myopic chorioretinitis and retinal dystrophy; wife, age 65, with mild symptoms; daughter, age 29, asymptomatic...
March 10, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28285324/novel-therapeutics-for-stargardt-disease
#10
REVIEW
Louise J Lu, Ji Liu, Ron A Adelman
DESCRIPTION OF SITUATION: Stargardt disease, an inherited macular dystrophy caused by mutations in the ABCA4 gene encoding a retinal transporter protein, is the most prevalent form of macular degeneration in children. Patients with Stargardt disease develop severe vision loss within their first or second decades of life, which progresses to irreversible decreased visual acuity in almost all cases. Presently, there are no standard treatments for Stargardt disease. However, encouraging progress has been made in the development of innovative approaches to preventing vision loss in Stargardt patients...
March 11, 2017: Graefe's Archive for Clinical and Experimental Ophthalmology
https://www.readbyqxmd.com/read/28248825/ultrawidefield-autofluoresence-in-abca4-stargardt-disease
#11
Michael A Klufas, Irena Tsui, SriniVas R Sadda, Hamid Hosseini, Steven D Schwartz
PURPOSE: To report the ultrawidefield fundus autofluorescence (UWF-FAF) patterns in ABC4A Stargardt disease. METHODS: A retrospective cohort study of patients with a clinical diagnosis of Stargardt disease, confirmed ABCA4 genotype, and ultrawidefield fundus autofluorescence imaging using an Optos P200Tx. Four independent graders evaluated the images. Ultrawidefield fundus autofluorescence images were evaluated for the presence of posterior pole and peripheral findings, and were classified into one of three types (Type I: lesions confined to the macula with no peripheral findings; Type II: macular atrophy with flecks only in the periphery; Type III: macular atrophy and varying degrees of peripheral atrophy)...
February 28, 2017: Retina
https://www.readbyqxmd.com/read/28239514/a-fragmented-adeno-associated-viral-dual-vector-strategy-for-treatment-of-diseases-caused-by-mutations-in-large-genes-leads-to-expression-of-hybrid-transcripts
#12
Michelle E McClements, Peter Charbel Issa, Véronique Blouin, Robert E MacLaren
OBJECTIVE: Dual vector AAV systems are being utilised to enable gene therapy for disorders in which the disease gene is too large to fit into a single capsid. Fragmented adeno-associated viral (fAAV) vectors containing single inverted terminal repeat truncated transgenes have been considered as one such gene replacement strategy. Here we aim to add to the current understanding of the molecular mechanisms employed by fAAV dual vector systems. METHODS: Oversized (>8kb) transgene constructs containing ABCA4 coding sequence were packaged as truncated fragments <5kb in size into various AAV serotypes...
November 14, 2016: Journal of Genetic Syndrome & Gene Therapy
https://www.readbyqxmd.com/read/28219732/all-trans-retinal-levels-and-formation-of-lipofuscin-precursors-after-bleaching-in-rod-photoreceptors-from-wild-type-and-abca4-mice
#13
Leopold Adler, Chunhe Chen, Yiannis Koutalos
The accumulation of lipofuscin in the cells of the retinal pigment epithelium (RPE) is thought to play an important role in the development and progression of degenerative diseases of the retina. The bulk of RPE lipofuscin originates in reactions of the rhodopsin chromophore, retinal, with components of the photoreceptor outer segment. The 11-cis retinal isomer is generated in the RPE and supplied to rod photoreceptor outer segments where it is incorporated as the chromophore of rhodopsin. It is photoisomerized during light detection to all-trans and subsequently released by photoactivated rhodopsin as all-trans retinal, which is removed through reduction to all-trans retinol in a reaction requiring metabolic input in the form of NADPH...
February 2017: Experimental Eye Research
https://www.readbyqxmd.com/read/28192797/aberrant-buildup-of-all-trans-retinal-dimer-a-nonpyridinium-bisretinoid-lipofuscin-fluorophore-contributes-to-the-degeneration-of-the-retinal-pigment-epithelium
#14
Junli Zhao, Yi Liao, Jingmeng Chen, Xinran Dong, Zhan Gao, Houjian Zhang, Xiaodan Wu, Zuguo Liu, Yalin Wu
Purpose: Nondegradable fluorophores that accumulate as deleterious lipofuscin of RPE are involved in pathological mechanisms leading to the degeneration of RPE in AMD. A2E, a major component of RPE lipofuscin, could cause damage to RPE cells. Nevertheless, all-trans-retinal dimer (atRAL dimer) was found to be much more abundant than that of A2E in eyes of Abca4-/-Rdh8-/- double-knockout (DKO) mice, a rodent model showing the typical characteristics of retinopathies in AMD patients. Our aim was to elucidate the effect and mechanism of atRAL dimer-induced RPE degeneration...
February 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28149006/role-of-lipids-in-retinal-vascular-and-macular-disorders
#15
REVIEW
Gunjan Prakash, Rachit Agrawal, Tanie Natung
Retinal diseases are significant by increasing problem in every part of the world. While excellent treatment has emerged for various retinal diseases, treatment for early disease is lacking due to an incomplete understanding of all molecular events. With aging, there is a striking accumulation of neutral lipids in Bruch's membrane. These neutral lipids leads to the creation of a lipid wall at the same locations where drusen and basal linear deposit, pathognomonic lesions of Age-related macular degeneration, subsequently form...
March 2017: Indian Journal of Clinical Biochemistry: IJCB
https://www.readbyqxmd.com/read/28147405/prominent-optic-disc-featured-in-inherited-retinopathy
#16
M G Todorova, R I Bojinova, C Valmaggia, D F Schorderet
Background We investigated the relationship between prominent optic disc (POD) and inherited retinal dystrophy (IRD). Patients and Methods A cross-sectional consecutive study was performed in 10 children and 11 adults of 7 non-related families. We performed clinical phenotyping, including a detailed examination, fundus autofluorescence, and colour fundus and OCT imaging. Genetic testing was subsequently performed for all family members presenting retinal pathology. Results In 4 members of a 3-generation family, hyperfluorescent deposits on the surface of POD were related to a p...
February 1, 2017: Klinische Monatsblätter Für Augenheilkunde
https://www.readbyqxmd.com/read/28130426/genetic-analysis-of-10-pedigrees-with-inherited-retinal-degeneration-by-exome-sequencing-and-phenotype-genotype-association
#17
Pooja Biswas, Jacque L Duncan, Bruno Maranhao, Igor Kozak, Kari Branham, Luis Gabriel, Jonathan H Lin, Giulio Barteselli, Mili Navani, John Suk, Michelle Parke, Catherine Schlechter, Richard G Weleber, John R Heckenlively, Gislin Dagnelie, Pauline Lee, S Amer Riazuddin, Radha Ayyagari
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...
April 1, 2017: Physiological Genomics
https://www.readbyqxmd.com/read/28118664/mutation-spectrum-of-the-abca4-gene-in-335-stargardt-disease-patients-from-a-multicenter-german-cohort-impact-of-selected-deep-intronic-variants-and-common-snps
#18
Heidi L Schulz, Felix Grassmann, Ulrich Kellner, Georg Spital, Klaus Rüther, Herbert Jägle, Karsten Hufendiek, Philipp Rating, Cord Huchzermeyer, Maria J Baier, Bernhard H F Weber, Heidi Stöhr
Purpose: Stargardt disease (STGD1) is an autosomal recessive retinopathy, caused by mutations in the retina-specific ATP-binding cassette transporter (ABCA4) gene. To establish the mutational spectrum and to assess effects of selected deep intronic and common genetic variants on disease, we performed a comprehensive sequence analysis in a large cohort of German STGD1 patients. Methods: DNA samples of 335 STGD1 patients were analyzed for ABCA4 mutations in its 50 coding exons and adjacent intronic sequences by resequencing array technology or next generation sequencing (NGS)...
January 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28095140/prom1-gene-variations-in-brazilian-patients-with-macular-dystrophy
#19
Mariana Vallim Salles, Fabiana Louise Motta, Elton Dias da Silva, Patricia Varela Lima Teixeira, Kárita Antunes Costa, Rafael Filippelli-Silva, Renan Martin, João Bosco Pesquero, Juliana Maria Ferraz Sallum
BACKGROUND: Although the pathogenicity of the prominin-1 (PROM1) gene has already been described as associated with autosomal dominant Stargardt disease, little is known about sequence variations in this gene. PURPOSE: The aim of this study was to evaluate PROM1 gene sequence variations in patients with macular dystrophy. MATERIAL AND METHODS: This retrospective study evaluated variations in the PROM1 gene detected by next-generation sequencing test in patients with macular dystrophy and Stargardt disease...
January 2017: Ophthalmic Genetics
https://www.readbyqxmd.com/read/28061825/new-cdh3-mutation-in-the-first-spanish-case-of-hypotrichosis-with-juvenile-macular-dystrophy-a-case-report
#20
Fiona Blanco-Kelly, Luciana Rodrigues-Jacy da Silva, Iker Sanchez-Navarro, Rosa Riveiro-Alvarez, Miguel Angel Lopez-Martinez, Marta Corton, Carmen Ayuso
BACKGROUND: CDH3 on 16q22.1 is responsible for two rare autosomal recessive disorders with hypotrichosis and progressive macular dystrophy: Hypotrichosis with Juvenile Macular Dystrophy and Ectodermal Dysplasia, Ectrodactyly and Macular Dystrophy. We present a new case of Hypotrichosis with Juvenile Macular Dystrophy. CASE PRESENTATION: A Spanish male born in 1998 from non-consanguineous healthy parents with a suspected diagnosis of Keratosis Follicularis Spinulosa Decalvans and Retinitis Pigmentosa Inversa referred to our Genetics Department (IIS-Fundación Jiménez Díaz)...
January 7, 2017: BMC Medical Genetics
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