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Brian P Hafler
PURPOSE: Inherited retinal dystrophies are a significant cause of vision loss and are characterized by the loss of photoreceptors and the retinal pigment epithelium (RPE). Mutations in approximately 250 genes cause inherited retinal degenerations with a high degree of genetic heterogeneity. New techniques in next-generation sequencing are allowing the comprehensive analysis of all retinal disease genes thus changing the approach to the molecular diagnosis of inherited retinal dystrophies...
October 6, 2016: Retina
Jie Li, Yanli Zhang, Xianhui Cai, Qingqing Xia, Jingmeng Chen, Yi Liao, Zuguo Liu, Yalin Wu
Effective clearance of all-trans-retinal (atRAL) from retinal pigment epithelial (RPE) cells is important for avoiding its cytotoxicity. However, the metabolism of atRAL in RPE cells is poorly clarified. The present study was designed to analyze metabolic products of atRAL and to compare the cytotoxicity of atRAL versus its derivative all-trans-retinal dimer (atRAL-dimer) in human RPE cells. We found that all-trans-retinol (atROL) and a mixture of atRAL condensation metabolites including atRAL-dimer and A2E were generated after incubating RPE cells with atRAL for 6h, and the amount of atRAL-dimer was significantly higher than that of A2E...
October 14, 2016: Toxicology
Bing Lin, Xue-Bi Cai, Zhi-Li Zheng, Xiu-Feng Huang, Xiao-Ling Liu, Jia Qu, Zi-Bing Jin
Stargardt disease (STGD1) is a juvenile macular degeneration predominantly inherited in an autosomal recessive pattern, characterized by decreased central vision in the first 2 decades of life. The condition has a genetic basis due to mutation in the ABCA4 gene, and arises from the deposition of lipofuscin-like substance in the retinal pigmented epithelium (RPE) with secondary photoreceptor cell death. In this study, we describe the clinical and genetic features of Stargardt patients from four unrelated Chinese cohorts...
October 14, 2016: Scientific Reports
Maria A Parker, Dongseok Choi, Laura R Erker, Mark E Pennesi, Paul Yang, Elvira N Chegarnov, Peter N Steinkamp, Catherine L Schlechter, Claire-Marie Dhaenens, Saddek Mohand-Said, Isabelle Audo, Jose Sahel, Richard G Weleber, David J Wilson
PURPOSE: The goal of this analysis was to determine the test-retest variability of functional and structural measures from a cohort of patients with advanced forms of Stargardt Disease (STGD) participating in the SAR422459 (NCT01367444) gene therapy clinical trial. METHODS: Twenty-two participants, aged 24 to 66, diagnosed with advanced forms of STGD, with at least one pathogenic ABCA4 mutation on each chromosome participating in the SAR422459 (NCT01367444) gene therapy clinical trial, were screened over three visits within 3 weeks or less...
October 2016: Translational Vision Science & Technology
M A Alabdullatif, M A Al Dhaibani, M Y Khassawneh, A W El-Hattab
Chromosomal microarray (CMA) has significantly improved diagnosing copy number variations (CNVs). Single nucleotide polymorphism (SNP) arrays confer additional utility in detecting regions of homozygosity (ROH). Investigating ROH for genes associated with recessive disorders for follow-up sequencing can aid in diagnosis. In this study, we performed a retrospective review of clinical and molecular data for 227 individuals from a highly consanguineous population who previously had a CMA. Pathogenic CNVs were identified in 32 (14%) cases; ROH suggesting uniparental disomy (UPD) in three (1%) cases, and an additional 25 (11%) individuals were diagnosed with recessive disorders caused by mutations in ROH candidate genes, thereby increasing the CMA diagnostic yield to 26%...
September 22, 2016: Clinical Genetics
Stanley Lambertus, Moritz Lindner, Nathalie M Bax, Matthias M Mauschitz, Jennifer Nadal, Matthias Schmid, Steffen Schmitz-Valckenberg, Anneke I den Hollander, Bernhard H F Weber, Frank G Holz, Gert Jan van der Wilt, Monika Fleckenstein, Carel B Hoyng
Purpose: Identification of sensitive biomarkers is essential to determine potential effects of emerging therapeutic trials for Stargardt disease. This study aimed to describe the natural history of late-onset Stargardt, and demonstrates the accuracy of retinal pigment epithelium (RPE) atrophy progression as an outcome measure. Methods: We performed a retrospective cohort study collecting multicenter data from 47 patients (91 eyes) with late-onset Stargardt, defined by clinical phenotype, at least one ABCA4 mutation, and age at disease onset ≥ 45 years...
October 1, 2016: Investigative Ophthalmology & Visual Science
Ana Fakin, Anthony G Robson, Kaoru Fujinami, Anthony T Moore, Michel Michaelides, John Pei-Wen Chiang, Graham E Holder, Andrew R Webster
PURPOSE: We describe the phenotypes associated with nullizigosity and nine splicing mutations in the ABCA4 gene. METHODS: The study included 19 patients with biallelic null mutations (Group A, nullizygous), 27 with splicing mutations in the homozygous state or in trans with a null mutation (Group B), and 20 with p.G1961E in trans with a null mutation (Group C, control). Ages at onset and visual acuities were determined from medical histories. Area of decreased autofluorescence within a 30° × 30° fundus autofluorescence (FAF) image was measured with the Region Finder (N = 58)...
September 1, 2016: Investigative Ophthalmology & Visual Science
Hsiu-Huei Peng, Nai-Chung Chang, Kuo-Ting Chen, Jang-Jih Lu, Pi-Yueh Chang, Shih-Cheng Chang, Yah-Huei Wu-Chou, Yi-Ting Chou, Wanni Phang, Po-Jen Cheng
BACKGROUND: Nonsyndromic orofacial cleft is a common birth defect with a complex etiology, including multiple genetic and environmental risk factors. Recent whole genome analyses suggested associations between nonsyndromic orofacial cleft and up to 18 genetic risk loci (ABCA4, BMP4, CRISPLD2, GSTT1, FGF8, FGFR2, FOXE1, IRF6, MAFB, MSX1, MTHFR, MYH9, PDGFC, PVRL1, SUMO1, TGFA, TGFB3, and VAX1), each of which confers a different relative risk in different populations. We evaluate the nonsynonymous variants in these 18 genetic risk loci in nonsyndromic orofacial clefts and normal controls to clarify the specific variants in Taiwanese population...
2016: BMC Medical Genetics
Preena Tanna, Rupert W Strauss, Kaoru Fujinami, Michel Michaelides
Stargardt disease (STGD1; MIM 248200) is the most prevalent inherited macular dystrophy and is associated with disease-causing sequence variants in the gene ABCA4 Significant advances have been made over the last 10 years in our understanding of both the clinical and molecular features of STGD1, and also the underlying pathophysiology, which has culminated in ongoing and planned human clinical trials of novel therapies. The aims of this review are to describe the detailed phenotypic and genotypic characteristics of the disease, conventional and novel imaging findings, current knowledge of animal models and pathogenesis, and the multiple avenues of intervention being explored...
August 4, 2016: British Journal of Ophthalmology
Li Xuan Tan, Kimberly A Toops, Aparna Lakkaraju
The retinal pigment epithelium (RPE) is a key site of injury in inherited and age-related macular degenerations. Abnormal activation of the complement system is a feature of these blinding diseases, yet how the RPE combats complement attack is poorly understood. The complement cascade terminates in the cell-surface assembly of membrane attack complexes (MACs), which promote inflammation by causing aberrant signal transduction. Here, we investigated mechanisms crucial for limiting MAC assembly and preserving cellular integrity in the RPE and asked how these are compromised in models of macular degeneration...
August 2, 2016: Proceedings of the National Academy of Sciences of the United States of America
S R De Silva, P C Issa, M S Singh, D M Lipinski, A O Barnea-Cramer, N J Walker, A R Barnard, M W Hankins, R E MacLaren
Gene therapy using adeno-associated viral vectors (AAV) for the treatment of retinal degenerations has shown safety and efficacy in clinical trials. However, very high levels of vector expression may be necessary for the treatment of conditions such as Stargardt disease where a dual vector approach is potentially needed, or in optogenetic strategies for end-stage degeneration in order to achieve maximal light sensitivity. In this study, we assessed two vectors with single capsid mutations, rAAV2/2(Y444F) and rAAV2/8(Y733F) in their ability to transduce retina in the Abca4(-/-) and rd1 mouse models of retinal degeneration...
July 14, 2016: Gene Therapy
Lucia Galli-Resta, Benedetto Falsini, Giuseppe Rossi, Marco Piccardi, Lucia Ziccardi, Antonello Fadda, Angelo Minnella, Dario Marangoni, Giorgio Placidi, Francesca Campagna, Edoardo Abed, Matteo Bertelli, Monia Zuntini, Giovanni Resta
PURPOSE: To investigate bilateral symmetry of visual impairment in cone-rod dystrophy (CRD) patients and understand the feasibility of clinical trial designs treating one eye and using the untreated eye as an internal control. METHODS: This was a retrospective study of visual function loss measures in 436 CRD patients followed at the Ophthalmology Department of the Catholic University in Rome. Clinical measures considered were best-corrected visual acuity, focal macular cone electroretinogram (fERG), and Ganzfeld cone-mediated and rod-mediated electroretinograms...
July 1, 2016: Investigative Ophthalmology & Visual Science
Philipp L Müller, Rolf Fimmers, Martin Gliem, Frank G Holz, Peter Charbel Issa
PURPOSE: To investigate choroidal alterations in ABCA4-related retinopathy. METHODS: Mean choroidal thickness and subfoveal choroidal thickness were measured in the right eyes of 40 patients with ABCA4-related retinopathy using enhanced-depth imaging optical coherence tomography. The right eyes of 65 age-matched healthy subjects were used for comparison. RESULTS: Compared with controls, patients with ABCA4-related retinopathy revealed a reduced subfoveal choroidal thickness ([mean ± SEM] 347 ± 10 μm vs...
July 13, 2016: Retina
Srilekha Sundaramurthy, Meenakshi Swaminathan, Parveen Sen, Tharigopala Arokiasamy, Swati Deshpande, Neetha John, Rupali A Gadkari, Ashraf U Mannan, Nagasamy Soumittra
Inherited retinal degeneration (IRD) are a group of genetically heterogeneous disease of which retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are the most common and severe type. In our study we had taken three unrelated South Indian consanguineous IRD families. Homozygosity mapping was done using Affymetrix 250K Nsp1 GeneChip in each of LCA, Cone-Rod dystrophy (CRD) and autosomal recessive RP (arRP) families followed by targeted re-sequencing by next generation sequencing (NGS) on Illumina MiSeq...
July 7, 2016: Journal of Human Genetics
Winston Lee, Kaspar Schuerch, Yajing Xie, Jana Zernant, Stephen H Tsang, Janet R Sparrow, Rando Allikmets
PURPOSE: To describe the complex, overlapping phenotype expressed in a two generation family harboring pathogenic mutations in the ABCA4 and GPR143 genes. METHODS: Clinical evaluation of a two generation family included quantitative autofluorescence imaging (qAF, 488-nm excitation) using a modified confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference to account for varying laser power detector sensitivity, spectral-domain optical coherence tomography, and full-field ERG testing...
June 1, 2016: Investigative Ophthalmology & Visual Science
Rando Allikmets, Tobias Duncker, Winston Lee, Stephen H Tsang
No abstract text is available yet for this article.
June 1, 2016: Investigative Ophthalmology & Visual Science
Tanu Parmar, Vipul M Parmar, Eisuke Arai, Bhubanananda Sahu, Lindsay Perusek, Akiko Maeda
PURPOSE: Mice lacking ATP-binding cassette transporter 4 (ABCA4) and retinol dehydrogenase 8 (RDH8) mimic features of human Stargardt disease and age-related macular degeneration. RNA-sequencing of whole eyes was done to study early gene expression changes in Abca4-/-Rdh8-/- mice. METHODS: Abca4-/-Rdh8-/- mice at 4 weeks of age were exposed to intense light. Total RNA was extracted from whole eyes and used to generate RNA libraries that were paired-end sequenced on the Illumina HiSeq 2500 device...
June 1, 2016: Investigative Ophthalmology & Visual Science
Keiko Ueda, Jin Zhao, Hye Jin Kim, Janet R Sparrow
Adducts of retinaldehyde (bisretinoids) form nonenzymatically in photoreceptor cells and accumulate in retinal pigment epithelial (RPE) cells as lipofuscin; these fluorophores are implicated in the pathogenesis of inherited and age-related macular degeneration (AMD). Here we demonstrate that bisretinoid photodegradation is ongoing in the eye. High-performance liquid chromatography (HPLC) analysis of eyes of dark-reared and cyclic light-reared wild-type mice, together with comparisons of pigmented versus albino mice, revealed a relationship between intraocular light and reduced levels of the bisretinoids A2E and A2-glycero-phosphoethanolamine (A2-GPE)...
June 21, 2016: Proceedings of the National Academy of Sciences of the United States of America
J A Velázquez-Aragón, M A Alcántara-Ortigoza, B Estandia-Ortega, M E Reyna-Fabián, C D Méndez-Adame, A González-Del Angel
Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a common craniofacial birth defect that has a complex etiology. Genome-wide association studies have recently identified new loci associated with NSCL/P, but these loci have not been analyzed in a Mexican Mestizo population. A complex etiology implies the presence of genetic interactions, but there is little available information regarding this in NSCL/P, and no signaling pathway has been clearly implicated in humans. Here, we analyzed the associations of 24 single nucleotide polymorphisms (SNPs) with NSCL/P in a Mexican Mestizo population (133 cases, 263 controls)...
October 2016: Journal of Dental Research
Samuel G Jacobson, Rodrigo Matsui, Alexander Sumaroka, Artur V Cideciyan
PURPOSE: We reviewed and illustrated the most optimal retinal structural measurements to make in stem cell clinical trials. METHODS: Optical coherence tomography (OCT) and autofluorescence (AF) imaging were used to evaluate patients with severe visual loss from nonsyndromic and syndromic retinitis pigmentosa (RP), ABCA4-Stargardt disease, and nonneovascular age-related macular degeneration (AMD). Outer nuclear layer (ONL), rod outer segment (ROS) layer, inner retina, ganglion cell layer (GCL), and nerve fiber layer (NFL) thicknesses were quantified...
April 1, 2016: Investigative Ophthalmology & Visual Science
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