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https://www.readbyqxmd.com/read/28327576/genotypic-spectrum-and-phenotype-correlations-of-abca4-associated-disease-in-patients-of-south-asian-descent
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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 17, 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
#8
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
#9
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
#10
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-ten-pedigrees-with-inherited-retinal-degeneration-ird-by-exome-sequencing-and-phenotype-genotype-association
#11
Pooja Biswas, Jacque L Duncan, Bruno Maranhao, Igor Kozak, Kari Branham, Luis Gabriel, Jonathan H Lin, Guilio Barteselli, Mili Navani, John J Suk, Michelle Parke, Catherine Schlechter, Richard Weleber, John R Heckenlively, Gislin Dagnelie, Pauline Lee, S Amer Riazuddin, Radha Ayyagari
PURPOSE: To identify causative mutations and characterize the phenotype associated with the genotype in ten unrelated families with autosomal recessive retinal degeneration. METHODS: Ophthalmic evaluation and DNA isolation was carried out in 10 pedigrees with IRD. Exomes of probands from 8 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 Jews ancestry...
January 27, 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
#12
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
#13
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
#14
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
https://www.readbyqxmd.com/read/28044389/in-silico-functional-meta-analysis-of-5-962-abca4-variants-in-3-928-retinal-dystrophy-cases
#15
Stéphanie S Cornelis, Nathalie M Bax, Jana Zernant, Rando Allikmets, Lars G Fritsche, Johan T den Dunnen, Muhammad Ajmal, Carel B Hoyng, Frans P M Cremers
Variants in the ABCA4 gene are associated with a spectrum of inherited retinal diseases (IRDs), most prominently with autosomal recessive (ar) Stargardt disease (STGD1) and ar cone-rod dystrophy. The clinical outcome to a large degree depends on the severity of the variants. To provide an accurate prognosis and to select patients for novel treatments, functional significance assessment of nontruncating ABCA4 variants is important. We collected all published ABCA4 variants from 3,928 retinal dystrophy cases in a Leiden Open Variation Database, and compared their frequency in 3,270 Caucasian IRD cases with 33,370 non-Finnish European control individuals...
April 2017: Human Mutation
https://www.readbyqxmd.com/read/28035529/hereditary-retinal-dystrophy
#16
Thomas C Hohman
As our understanding of the genetic basis for inherited retinal disease has expanded, gene therapy has advanced into clinical development. When the gene mutations associated with inherited retinal dystrophies were identified, it became possible to create animal models in which individual gene were altered to match the human mutations. The retina of these animals were then characterized to assess whether the mutated genes produced retinal phenotypes characteristic of disease-affected patients. Following the identification of a subpopulation of patients with the affected gene and the development of techniques for the viral gene transduction of retinal cells, it has become possible to deliver a copy of the normal gene into the retinal sites of the mutated genes...
December 30, 2016: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28005406/a-report-on-molecular-diagnostic-testing-for-inherited-retinal-dystrophies-by-targeted-genetic-analyses
#17
Hema L Ramkumar, Harini V Gudiseva, Kameron T Kishaba, John J Suk, Rohan Verma, Keerti Tadimeti, John A Thorson, Radha Ayyagari
AIM: To test the utility of targeted sequencing as a method of clinical molecular testing in patients diagnosed with inherited retinal degeneration (IRD). METHODS: After genetic counseling, peripheral blood was drawn from 188 probands and 36 carriers of IRD. Single gene testing was performed on each patient in a Clinical Laboratory Improvement Amendment (CLIA) certified laboratory. DNA was isolated, and all exons in the gene of interest were analyzed along with 20 base pairs of flanking intronic sequence...
February 2017: Genetic Testing and Molecular Biomarkers
https://www.readbyqxmd.com/read/28002570/asymmetric-inter-eye-progression-in-stargardt-disease
#18
Stanley Lambertus, Nathalie M Bax, Joannes M M Groenewoud, Frans P M Cremers, Gert Jan van der Wilt, B Jeroen Klevering, Thomas Theelen, Carel B Hoyng
Purpose: Asymmetry in disease progression between left and right eyes can occur in Stargardt disease (STGD1), and this needs to be considered in novel therapeutic trials with a fellow-eye paired controlled design. This study investigated the inter-eye discordance of best-corrected visual acuity (BCVA) and progression of RPE atrophy in STGD1. Methods: We performed a retrospective cohort study collecting 68 STGD1 patients (136 eyes) with ≥1 ABCA4 variants and ≥0...
December 1, 2016: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/27992460/norbixin-protects-retinal-pigmented-epithelium-cells-and-photoreceptors-against-a2e-mediated-phototoxicity-in-vitro-and-in-vivo
#19
Valérie Fontaine, Elodie Monteiro, Elena Brazhnikova, Laëtitia Lesage, Christine Balducci, Louis Guibout, Laurence Feraille, Pierre-Paul Elena, José-Alain Sahel, Stanislas Veillet, René Lafont
The accumulation of N-retinylidene-N-retinylethanolamine (A2E, a toxic by-product of the visual pigment cycle) in the retinal pigment epithelium (RPE) is a major cause of visual impairment in the elderly. Photooxidation of A2E results in retinal pigment epithelium degeneration followed by that of associated photoreceptors. Present treatments rely on nutrient supplementation with antioxidants. 9'-cis-Norbixin (a natural diapocarotenoid, 97% purity) was prepared from Bixa orellana seeds. It was first evaluated in primary cultures of porcine retinal pigment epithelium cells challenged with A2E and illuminated with blue light, and it provided an improved photo-protection as compared with lutein or zeaxanthin...
2016: PloS One
https://www.readbyqxmd.com/read/27939946/stargardt-disease-associated-mutation-spectrum-of-a-russian-federation-cohort
#20
Inna V Zolnikova, Vladimir V Strelnikov, Natalia A Skvortsova, Alexander S Tanas, Debmalya Barh, Elena V Rogatina, Irina V Egorova, Darja V Levina, Olga N Demenkova, Egor G Prikaziuk, Marianna E Ivanova
ABCA4-associated mutation screening is extensively performed in European, African, American and several other populations for various retinopathies. However, it has not been well studied in a Russian cohort. Using next-generation (325 genes inherited disease panel) and Sanger sequencing technologies for the first time we documented the spectrum of genetic variations in a Russian retinopathy cohort of 51 patients from 10 ethnic groups. We found ABCA4 variations in 70.5% cases and one case with BEST1 variation...
February 2017: European Journal of Medical Genetics
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