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https://www.readbyqxmd.com/read/29773803/a-novel-small-molecule-chaperone-of-rod-opsin-and-its-potential-therapy-for-retinal-degeneration
#1
Yuanyuan Chen, Yu Chen, Beata Jastrzebska, Marcin Golczak, Sahil Gulati, Hong Tang, William Seibel, Xiaoyu Li, Hui Jin, Yong Han, Songqi Gao, Jianye Zhang, Xujie Liu, Hossein Heidari-Torkabadi, Phoebe L Stewart, William E Harte, Gregory P Tochtrop, Krzysztof Palczewski
Rhodopsin homeostasis is tightly coupled to rod photoreceptor cell survival and vision. Mutations resulting in the misfolding of rhodopsin can lead to autosomal dominant retinitis pigmentosa (adRP), a progressive retinal degeneration that currently is untreatable. Using a cell-based high-throughput screen (HTS) to identify small molecules that can stabilize the P23H-opsin mutant, which causes most cases of adRP, we identified a novel pharmacological chaperone of rod photoreceptor opsin, YC-001. As a non-retinoid molecule, YC-001 demonstrates micromolar potency and efficacy greater than 9-cis-retinal with lower cytotoxicity...
May 17, 2018: Nature Communications
https://www.readbyqxmd.com/read/29769798/novel-variants-identified-with-next-generation-sequencing-in-polish-patients-with-cone-rod-dystrophy
#2
Anna Wawrocka, Anna Skorczyk-Werner, Katarzyna Wicher, Zuzanna Niedziela, Rafal Ploski, Malgorzata Rydzanicz, Maciej Sykulski, Jaroslaw Kociecki, Nicole Weisschuh, Susanne Kohl, Saskia Biskup, Bernd Wissinger, Maciej R Krawczynski
Purpose: The aim of this study was to identify the molecular genetic basis of cone-rod dystrophy in 18 unrelated families of Polish origin. Cone-rod dystrophy is one of the inherited retinal dystrophies, which constitute a highly heterogeneous group of disorders characterized by progressive dysfunction of photoreceptors and retinal pigment epithelium (RPE) cells. Methods: The study group was composed of four groups of patients representing different Mendelian inheritance of the disease: autosomal dominant (AD), autosomal recessive (AR), X-linked recessive (XL), and autosomal recessive or X-linked recessive (AR/XL)...
2018: Molecular Vision
https://www.readbyqxmd.com/read/29736279/phenotypic-progression-of-stargardt-disease-in-a-large-consanguineous-tunisian-family-harboring-new-abca4-mutations
#3
Yousra Falfoul, Imen Habibi, Ahmed Turki, Ahmed Chebil, Asma Hassairi, Daniel F Schorderet, Leila El Matri
To assess the progression of Stargardt (STGD) disease over nine years in two branches of a large consanguineous Tunisian family. Initially, different phenotypes were observed with clinical intra- and interfamilial variations. At presentation, four different retinal phenotypes were observed. In phenotype 1, bull's eye maculopathy and slight alteration of photopic responses in full-field electroretinography were observed in the youngest child. In phenotype 2, macular atrophy and yellow white were observed in two brothers...
2018: Journal of Ophthalmology
https://www.readbyqxmd.com/read/29725296/the-p2y-12-receptor-antagonist-ticagrelor-reduces-lysosomal-ph-and-autofluorescence-in-retinal-pigmented-epithelial-cells-from-the-abca4-mouse-model-of-retinal-degeneration
#4
Wennan Lu, Néstor M Gómez, Jason C Lim, Sonia Guha, Ann O'Brien-Jenkins, Erin E Coffey, Keith E Campagno, Stuart A McCaughey, Alan M Laties, Leif G Carlsson, Claire H Mitchell
The accumulation of partially degraded lipid waste in lysosomal-related organelles may contribute to pathology in many aging diseases. The presence of these lipofuscin granules is particularly evident in the autofluorescent lysosome-associated organelles of the retinal pigmented epithelial (RPE) cells, and may be related to early stages of age-related macular degeneration. While lysosomal enzymes degrade material optimally at acidic pH levels, lysosomal pH is elevated in RPE cells from the ABCA4-/- mouse model of Stargardt's disease, an early onset retinal degeneration...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29686088/iron-promotes-oxidative-cell-death-caused-by-bisretinoids-of-retina
#5
Keiko Ueda, Hye Jin Kim, Jin Zhao, Ying Song, Joshua L Dunaief, Janet R Sparrow
Intracellular Fe plays a key role in redox active energy and electron transfer. We sought to understand how Fe levels impact the retina, given that retinal pigment epithelial (RPE) cells are also challenged by accumulations of vitamin A aldehyde adducts (bisretinoid lipofuscin) that photogenerate reactive oxygen species and photodecompose into damaging aldehyde- and dicarbonyl-bearing species. In mice treated with the Fe chelator deferiprone (DFP), intracellular Fe levels, as reflected in transferrin receptor mRNA expression, were reduced...
April 23, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29625472/visual-cortex-activation-in-patients-with-stargardt-disease
#6
Paolo Melillo, Anna Prinster, Valentina Di Iorio, Gaia Olivo, Francesco Maria D'Alterio, Sirio Cocozza, Ada Orrico, Mario Quarantelli, Francesco Testa, Arturo Brunetti, Francesca Simonelli
Purpose: Primary visual cortex (PVC) contains a retinotopic map in which the central visual field (CVF) is highly magnified compared to the peripheral field. Several studies have used functional magnetic resonance imaging (fMRI) in patients with macular degeneration to assess the reorganization of visual processing in relationship with the development of extrafoveal preferred retinal locus (PRL). We evaluated the functional response in PVC and its correlation with retinal parameters in patients with Stargardt disease due to ABCA4 mutations (STGD1)...
March 1, 2018: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/29602770/lipocalin-2-plays-an-important-role-in-regulating-inflammation-in-retinal-degeneration
#7
Tanu Parmar, Vipul M Parmar, Lindsay Perusek, Anouk Georges, Masayo Takahashi, John W Crabb, Akiko Maeda
It has become increasingly important to understand how retinal inflammation is regulated because inflammation plays a role in retinal degenerative diseases. Lipocalin 2 (LCN2), an acute stress response protein with multiple innate immune functions, is increased in ATP-binding cassette subfamily A member 4 ( Abca4 ) -/- retinol dehydrogenase 8 ( Rdh8 ) -/- double-knockout mice, an animal model for Stargardt disease and age-related macular degeneration (AMD). To examine roles of LCN2 in retinal inflammation and degeneration, Lcn2-/- Abca4-/- Rdh8-/- triple-knockout mice were generated...
March 30, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29566461/surfactant-deficiency-syndrome-in-an-infant-with-a-c-terminal-frame-shift-in-abca3-a-case-report
#8
Nour Akil, Anthony J Fischer
Deficiency in ATP binding cassette A3 (ABCA3) causes neonatal respiratory distress, hypoxemic respiratory failure, and interstitial lung disease. ABCA3 transports phospholipids into the lamellar bodies of type II alveolar cells, a critical step in alveolar surfactant production. We report a term infant with ABCA3 surfactant deficiency syndrome with the E292V (c.875A>T; p.Glu292Val) mutation in trans with a novel C-terminal frame shift mutation (c.4938delC; p.Met1647fs). This mutation removes the final 58 amino acids and substitutes 33 incorrect amino acids...
March 22, 2018: Pediatric Pulmonology
https://www.readbyqxmd.com/read/29555955/clinical-and-genetic-characteristics-of-251-consecutive-patients-with-macular-and-cone-cone-rod-dystrophy
#9
Johannes Birtel, Tobias Eisenberger, Martin Gliem, Philipp L Müller, Philipp Herrmann, Christian Betz, Diana Zahnleiter, Christine Neuhaus, Steffen Lenzner, Frank G Holz, Elisabeth Mangold, Hanno J Bolz, Peter Charbel Issa
Macular and cone/cone-rod dystrophies (MD/CCRD) demonstrate a broad genetic and phenotypic heterogeneity, with retinal alterations solely or predominantly involving the central retina. Targeted next-generation sequencing (NGS) is an efficient diagnostic tool for identifying mutations in patient with retinitis pigmentosa, which shows similar genetic heterogeneity. To detect the genetic causes of disease in patients with MD/CCRD, we implemented a two-tier procedure consisting of Sanger sequencing and targeted NGS including genes associated with clinically overlapping conditions...
March 19, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29526278/identification-and-rescue-of-splice-defects-caused-by-two-neighboring-deep-intronic-abca4-mutations-underlying-stargardt-disease
#10
Silvia Albert, Alejandro Garanto, Riccardo Sangermano, Mubeen Khan, Nathalie M Bax, Carel B Hoyng, Jana Zernant, Winston Lee, Rando Allikmets, Rob W J Collin, Frans P M Cremers
Sequence analysis of the coding regions and splice site sequences in inherited retinal diseases is not able to uncover ∼40% of the causal variants. Whole-genome sequencing can identify most of the non-coding variants, but their interpretation is still very challenging, in particular when the relevant gene is expressed in a tissue-specific manner. Deep-intronic variants in ABCA4 have been associated with autosomal-recessive Stargardt disease (STGD1), but the exact pathogenic mechanism is unknown. By generating photoreceptor precursor cells (PPCs) from fibroblasts obtained from individuals with STGD1, we demonstrated that two neighboring deep-intronic ABCA4 variants (c...
April 5, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29470301/a-case-of-intraretinal-peripapillary-neovascularization-in-abca4-related-retinopathy
#11
Juliet O Essilfie, An Huynh, Michael B Gorin, SriniVas R Sadda
PURPOSE: To report a case of ABCA4-related retinopathy and potential complications. METHODS: The authors describe a case report of intraretinal neovascularization in a patient with ABCA4-related retinopathy and describe the multimodal retinal imaging findings. RESULTS: A 49-year-old woman presents with cystoid macular edema and diffuse intraretinal and perivascular hyperpigmentation in both eyes. Genetic testing confirmed ABCA4-related retinopathy...
February 21, 2018: Retinal Cases & Brief Reports
https://www.readbyqxmd.com/read/29461686/atp-binding-cassette-subfamily-a-member-4-intronic-variants-c-4773-3a-g-and-c-5461-10t-c-cause-stargardt-disease-due-to-defective-splicing
#12
Frida Jonsson, Ida Maria Westin, Lennart Österman, Ola Sandgren, Marie Burstedt, Monica Holmberg, Irina Golovleva
PURPOSE: Inherited retinal dystrophies (IRDs) represent a group of progressive conditions affecting the retina. There is a great genetic heterogeneity causing IRDs, and to date, more than 260 genes are associated with IRDs. Stargardt disease, type 1 (STGD1) or macular degeneration with flecks, STGD1 represents a disease with early onset, central visual impairment, frequent appearance of yellowish flecks and mutations in the ATP-binding cassette subfamily A, member 4 (ABCA4) gene. A large number of intronic sequence variants in ABCA4 have been considered pathogenic although their functional effect was seldom demonstrated...
February 20, 2018: Acta Ophthalmologica
https://www.readbyqxmd.com/read/29437900/identification-of-a-novel-mutation-in-the-abca4-gene-in-a-chinese-family-with-retinitis-pigmentosa-using-exome-sequencing
#13
Xiangjun Huang, Lamei Yuan, Hongbo Xu, Wen Zheng, Yanna Cao, Junhui Yi, Yi Guo, Zhijian Yang, Yu Li, Hao Deng
Retinitis pigmentosa (RP) is a group of hereditary, degenerative retinal disorders characterized by progressive retinal dysfunction, outer retina cell loss, and retinal tissue atrophy. It eventually leads to tunnel vision and legal, or total blindness. Here we aimed to reveal the causal gene and mutation contributing to the development of autosomal recessive RP (arRP) in a consanguineous family. A novel homozygous mutation, c.4845delT (p.K1616Rfs*46), in the ATP-binding cassette subfamily A member 4gene ( ABCA4 ) was identified...
February 5, 2018: Bioscience Reports
https://www.readbyqxmd.com/read/29422768/retinal-phenotypic-characterization-of-patients-with-abca4-retinopathydue-to-the-homozygous-p-ala1773val-mutation
#14
Salvador López-Rubio, Oscar F Chacon-Camacho, Rodrigo Matsui, Dalia Guadarrama-Vallejo, Mirena C Astiazarán, Juan C Zenteno
Purpose: To describe the retinal clinical features of a group of Mexican patients with Stargardt disease carrying the uncommon p.Ala1773Val founder mutation in ABCA4 . Methods: Ten patients carrying the p.Ala1773Val mutation, nine of them homozygously, were included. Visual function studies included best-corrected visual acuity, electroretinography, Goldmann kinetic visual fields, and full-field electroretinography (ERG). In addition, imaging studies, such as optical coherence tomography (OCT), short-wave autofluorescence imaging, and quantitative analyses of hypofluorescence, were performed in each patient...
2018: Molecular Vision
https://www.readbyqxmd.com/read/29401616/new-gaba-modulators-protect-photoreceptor-cells-from-light-induced-degeneration-in-mouse-models
#15
Rebecca M Schur, Songqi Gao, Guanping Yu, Yu Chen, Akiko Maeda, Krzysztof Palczewski, Zheng-Rong Lu
No clinically approved therapies are currently available that prevent the onset of photoreceptor death in retinal degeneration. Signaling between retinal neurons is regulated by the release and uptake of neurotransmitters, wherein GABA is the main inhibitory neurotransmitter. In this work, novel 3-chloropropiophenone derivatives and the clinical anticonvulsants tiagabine and vigabatrin were tested to modulate GABA signaling and protect against light-induced retinal degeneration. Abca4-/- Rdh8-/- mice, an accelerated model of retinal degeneration, were exposed to intense light after prophylactic injections of one of these compounds...
January 24, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29386879/full-field-erg-as-a-predictor-of-the-natural-course-of-abca4-associated-retinal-degenerations
#16
Marion Schroeder, Ulrika Kjellström
Purpose: To assess retinal function in combination with the retinal structure in ABCA4 -associated retinal degenerations. Moreover, to evaluate the possibility of predicting the natural course of these disorders. Methods: 34 patients with Stargardt disease or cone rod dystrophy carrying confirmed mutations in ABCA4 were selected from our retinitis pigmentosa (RP) register. Sequence analysis of the entire coding region of the ABCA4 gene was performed. The patients were subdivided into three groups based on their most recent visual fields...
2018: Molecular Vision
https://www.readbyqxmd.com/read/29310964/early-patterns-of-macular-degeneration-in-abca4-associated-retinopathy
#17
Kamron N Khan, Melissa Kasilian, Omar A R Mahroo, Preena Tanna, Angelos Kalitzeos, Anthony G Robson, Kazushige Tsunoda, Takeshi Iwata, Anthony T Moore, Kaoru Fujinami, Michel Michaelides
PURPOSE: To describe the earliest features of ABCA4-associated retinopathy. DESIGN: Case series. PARTICIPANTS: Children with a clinical and molecular diagnosis of ABCA4-associated retinopathy without evidence of macular atrophy. METHODS: The retinal phenotype was characterized by color fundus photography, OCT, fundus autofluorescence (FAF) imaging, electroretinography, and in 2 patients, adaptive optics scanning laser ophthalmoscopy (AOSLO)...
January 5, 2018: Ophthalmology
https://www.readbyqxmd.com/read/29229934/bis-monoacylglycero-phosphate-lipids-in-the-retinal-pigment-epithelium-implicate-lysosomal-endosomal-dysfunction-in-a-model-of-stargardt-disease-and-human-retinas
#18
David M G Anderson, Zsolt Ablonczy, Yiannis Koutalos, Anne M Hanneken, Jeffrey M Spraggins, M Wade Calcutt, Rosalie K Crouch, Richard M Caprioli, Kevin L Schey
Stargardt disease is a juvenile onset retinal degeneration, associated with elevated levels of lipofuscin and its bis-retinoid components, such as N-retinylidene-N-retinylethanolamine (A2E). However, the pathogenesis of Stargardt is still poorly understood and targeted treatments are not available. Utilizing high spatial and high mass resolution matrix assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS), we determined alterations of lipid profiles specifically localized to the retinal pigment epithelium (RPE) in Abca4-/- Stargardt model mice compared to their relevant background strain...
December 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29207047/clinical-and-next-generation-sequencing-findings-in-a-chinese-family-exhibiting-severe-familial-exudative-vitreoretinopathy
#19
Ying Lin, Hongbin Gao, Chuan Chen, Yi Zhu, Tao Li, Bingqian Liu, Chenghong Ma, Hongye Jiang, Yonghao Li, Ying Huang, Qingxiu Wu, Haichun Li, Xiaoling Liang, Chenjin Jin, Jianhua Ye, Xinhua Huang, Lin Lu
Familial exudative vitreoretinopathy (FEVR) is a rare hereditary retinal disorder characterized by the premature arrest of vascularization in the peripheral retina. The aim of the present study was to characterize the clinical presentations of a Chinese family affected by bilateral severe FEVR, and to identify the underlying genetic variations. One family that presented with bilateral FEVR was recruited for this study. Comprehensive ophthalmic examinations, including best‑corrected visual acuity, slit‑lamp examination, fundus photography, fundus fluorescein angiography imaging and electroretinogram were performed...
February 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29188512/dual-aav-vectors-for-stargardt-disease
#20
Ivana Trapani
Stargardt disease (STGD1), due to mutations in the large ABCA4 gene, is the most common inherited macular degeneration in humans. Attempts at developing gene therapy approaches for treatment of STGD1 are currently ongoing. Among all the vectors available for gene therapy of inherited retinal diseases, those based on adeno-associated viruses (AAV) are the most promising given the efficacy shown in various animal models and their excellent safety profile in humans, as confirmed in many ongoing clinical trials...
2018: Methods in Molecular Biology
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