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11 results on '"Juliette Wohlschlegel"'

1. Single cell dual-omic atlas of the human developing retina

Author

Zhen Zuo, Xuesen Cheng, Salma Ferdous, Jianming Shao, Jin Li, Yourong Bao, Jean Li, Jiaxiong Lu, Antonio Jacobo Lopez, Juliette Wohlschlegel, Aric Prieve, Mervyn G. Thomas, Thomas A. Reh, Yumei Li, Ala Moshiri, and Rui Chen

Subjects
Science
Abstract

Abstract The development of the retina is under tight temporal and spatial control. To gain insights into the molecular basis of this process, we generate a single-nuclei dual-omic atlas of the human developing retina with approximately 220,000 nuclei from 14 human embryos and fetuses aged between 8 and 23-weeks post-conception with matched macular and peripheral tissues. This atlas captures all major cell classes in the retina, along with a large proportion of progenitors and cell-type-specific precursors. Cell trajectory analysis reveals a transition from continuous progression in early progenitors to a hierarchical development during the later stages of cell type specification. Both known and unrecorded candidate transcription factors, along with gene regulatory networks that drive the transitions of various cell fates, are identified. Comparisons between the macular and peripheral retinae indicate a largely consistent yet distinct developmental pattern. This atlas offers unparalleled resolution into the transcriptional and chromatin accessibility landscapes during development, providing an invaluable resource for deeper insights into retinal development and associated diseases.

Published
2024
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2. Generation of human induced pluripotent stem cell lines from a subject with UBAP1L-associated retinal dystrophy and CRISPR/cas9-corrected isogenic iPSC lines

Author

Andréa Amprou, Tasnim Ben Yacoub, Camille Letellier, Vincenzo Degaetano, Cécile Méjécase, Leila Azizzadeh Pormehr, Christel Condroyer, Amélie Slembrouck-Brec, Juliette Wohlschlegel, Olivier Goureau, Christina Zeitz, and Isabelle Audo

Subjects
Biology (General), QH301-705.5
Abstract

A Human induced pluripotent stem cell (iPSC) line was generated from dermal fibroblasts of a patient affected with an autosomal recessive retinal dystrophy carrying the homozygous c.910-7G>A variant in UBAP1L. Three isogenic control iPSC lines derived from this affected subject line were created using CRISPR/Cas9 engineering. All iPSC lines expressing the pluripotency markers, were able to differentiate into the three germ layers, and exhibit a normal karyotype. These cellular models will provide a powerful tool to study disease mechanisms associated with the recently reported UBAP1L- associated retinal dystrophy and better understand the role of the protein in retinal physiology.

Published
2024
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3. Generation of gene corrected human isogenic iPSC lines (IDVi003-A_CR13, IDVi003-A_CR21, IDVi003-A_CR24) from an inherited retinal dystrophy patient-derived IPSC line ITM2B-5286-3 (IDVi003-A) carrying the ITM2B c.782A > C variant using CRISPR/Cas9

Author

Tasnim Ben yacoub, Camille Letellier, Juliette Wohlschlegel, Christel Condroyer, Amélie Slembrouck-Brec, Olivier Goureau, Christina Zeitz, and Isabelle Audo

Subjects
Biology (General), QH301-705.5
Abstract

The ITM2B-related retinal dystrophy (ITM2B-RD) was identified within patients carrying the autosomal dominant variant [c.782A > C, p.(Glu261Ala)] in ITM2B from whom induced pluripotent stem cell (IPSC) lines were previously generated. Here, we report the generation of three isogenic control iPSC lines from the derived affected subject cell line (ITM2B-5286-3) using CRISPR/Cas9 engineering. The three generated lines express pluripotency markers, can be differentiated into the three germ layers and present a normal karyotype. The generated iPSC lines can be used to study the implications of ITM2B-RD variant in vitro.

Published
2023
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4. Identification and characterization of novel TRPM1 autoantibodies from serum of patients with melanoma-associated retinopathy.

Author

Juliette Varin, Margaret M Reynolds, Nassima Bouzidi, Sarah Tick, Juliette Wohlschlegel, Ondine Becquart, Christelle Michiels, Olivier Dereure, Robert M Duvoisin, Catherine W Morgans, José-Alain Sahel, Quentin Samaran, Bernard Guillot, José S Pulido, Isabelle Audo, and Christina Zeitz

Subjects
Medicine, Science
Abstract

Melanoma-associated retinopathy (MAR) is a rare paraneoplastic retinal disorder usually occurring in the context of metastatic melanoma. Patients present with night blindness, photopsias and a constriction of the visual field. MAR is an auto-immune disorder characterized by the production of autoantibodies targeting retinal proteins, especially autoantibodies reacting to the cation channel TRPM1 produced in melanocytes and ON-bipolar cells. TRPM1 has at least three different isoforms which vary in the N-terminal region of the protein. In this study, we report the case of three new MAR patients presenting different anti-TRPM1 autoantibodies reacting to the three isoforms of TRPM1 with variable binding affinity. Two sera recognized all isoforms of TRPM1, while one recognized only the two longest isoforms upon immunolocalization studies on overexpressing cells. Similarly, the former two sera reacted with all TRPM1 isoforms on western blot, but an immunoprecipitation enrichment step was necessary to detect all isoforms with the latter serum. In contrast, all sera labelled ON-bipolar cells on Tprm1+/+ but not on Trpm1-/- mouse retina as shown by co-immunolocalization. This confirms that the MAR sera specifically detect TRPM1. Most likely, the anti-TRPM1 autoantibodies of different patients vary in affinity and concentration. In addition, the binding of autoantibodies to TRPM1 may be conformation-dependent, with epitopes being inaccessible in some constructs (truncated polypeptides versus full-length TRPM1) or applications (western blotting versus immunohistochemistry). Therefore, we propose that a combination of different methods should be used to test for the presence of anti-TRPM1 autoantibodies in the sera of MAR patients.

Published
2020
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5. Generation of human induced pluripotent stem cell lines from a patient with ITM2B-related retinal dystrophy and a non mutated brother

Author

Juliette Wohlschlegel, Camille Letellier, Bingqian Liu, Cécile Méjécase, Amélie Slembrouck-Brec, Christel Condroyer, Christelle Michiels, José-Alain Sahel, Sacha Reichman, Christina Zeitz, Olivier Goureau, and Isabelle Audo

Subjects
Biology (General), QH301-705.5
Abstract

Human induced pluripotent stem cell (iPSC) lines were generated from fibroblasts of a patient affected with an autosomal dominant retinal dystrophy carrying the mutation c.782A>C, p.Glu261Ala in ITM2B and from an unaffected brother. Three different iPSC lines were generated and characterized from primary dermal fibroblasts of the affected subject and two from the unaffected brother. All iPSC lines expressed the pluripotency markers, were able to differentiate into the three germ layers and presented normal karyotypes. This cellular model will provide a powerful tool to study this retinal dystrophy and better understand the role of ITM2B.

Published
2019
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6. Reprogramming Müller glia to regenerate ganglion-like cells in adult mouse retina with developmental transcription factors

Author

Levi Todd, Wesley Jenkins, Connor Finkbeiner, Marcus J. Hooper, Phoebe C. Donaldson, Marina Pavlou, Juliette Wohlschlegel, Norianne Ingram, Fred Rieke, and Thomas A. Reh

Subjects
Neurons, Mammals, Mice, Multidisciplinary, Animals, Neuroglia, Retina, Transcription Factors
Abstract

Many neurodegenerative diseases cause degeneration of specific types of neurons. For example, glaucoma leads to death of retinal ganglion cells, leaving other neurons intact. Neurons are not regenerated in the adult mammalian central nervous system. However, in nonmammalian vertebrates, glial cells spontaneously reprogram into neural progenitors and replace neurons after injury. We have recently developed strategies to stimulate regeneration of functional neurons in the adult mouse retina by overexpressing the proneural factor Ascl1 in Müller glia. Here, we test additional transcription factors (TFs) for their ability to direct regeneration to particular types of retinal neurons. We engineered mice to express different combinations of TFs in Müller glia, including Ascl1, Pou4f2, Islet1, and Atoh1. Using immunohistochemistry, single-cell RNA sequencing, single-cell assay for transposase-accessible chromatin sequencing, and electrophysiology, we find that retinal ganglion–like cells can be regenerated in the damaged adult mouse retina in vivo with targeted overexpression of developmental retinal ganglion cell TFs.

Published
2022

7. Mutated CCDC51 Coding for a Mitochondrial Protein, MITOK Is a Candidate Gene Defect for Autosomal Recessive Rod-Cone Dystrophy

Author

Steven B. Blanchard, Cécile Méjécase, Thierry Léveillard, Sandra Chantot-Bastaraud, Marion Neuillé, Christelle Michiels, Saddek Mohand-Said, Elise Orhan, Christina Zeitz, Juliette Wohlschlegel, Frédéric Blond, Audrey Schalk, Sébastien Augustin, Christel Condroyer, Amrit Estivalet, Lisa Emmenegger, Aline Antonio, Vanessa Démontant, Crystel Bonnet, José-Alain Sahel, Camille Andrieu, Isabelle Audo, Marine Foussard, Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Genopole Research, Fondation Ophtalmologique Adolphe de Rothschild [Paris], Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UF de Génétique chromosomique [CHU Trousseau], CHU Trousseau [APHP], Académie des Sciences [Paris], Institut de France, Department of Ophthalmology [Pittsburgh, PA, États-Unis], University of Pittsburgh School of Medicine [Pittsburgh, PA, États-Unis], University of Pittsburgh Medical Center [Pittsburgh, PA, États-Unis] (UPMC)-University of Pittsburgh Medical Center [Pittsburgh, PA, États-Unis] (UPMC), Institute of Ophthalmology [London], University College of London [London] (UCL), This research was funded by Fondation Voir et Entendre (CZ), Prix Dalloz for 'La recherche en ophtalmologie' (CZ), LABEX LIFESENSES (reference ANR-10-LABX-65) supported by French state funds managed by the Agence Nationale de la Recherche within the Investissements d’Avenir program (ANR-11-IDEX-0004-0), IHU FOReSIGHT (ANR-18-IAHU-0001) supported by French state funds managed by the Agence Nationale de la Recherche within the Investissements d’Avenir program, Foundation Fighting Blindness center grant [C-CMM-0907-0428-INSERM04], grant (BR-GE-0619-0761-INSERM) Prix de la Fondation de l’Œil (IA), UNADEV (Union Nationale des Aveugles et Déficients Visuels) in partnership with ITMO NNP/AVIESAN (alliance nationale pour les sciences de la vie et de la santé) for research in visual disorders, and doctoral funding from the Ministère de l’Enseignement Supérieur et de la Recherche (MESR) and Fondation de France (CM)., ANR-10-LABX-0065,LIFESENSES,DES SENS POUR TOUTE LA VIE(2010), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), ANR-18-IAHU-0001,FOReSIGHT,Enabling Vision Restoration(2018), Couvet, Sandrine, DES SENS POUR TOUTE LA VIE - - LIFESENSES2010 - ANR-10-LABX-0065 - LABX - VALID, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, Enabling Vision Restoration - - FOReSIGHT2018 - ANR-18-IAHU-0001 - IAHU - VALID, Maladies génétiques d'expression pédiatrique (U933), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Male, Candidate gene, retina, Potassium Channels, [SDV]Life Sciences [q-bio], mitochondrial protein, 030105 genetics & heredity, Mitochondrion, medicine.disease_cause, Gene duplication, Biology (General), Spectroscopy, Genetics, Mutation, inner segments, MESH: Mitochondrial Proteins, General Medicine, MESH: Potassium Channels, Computer Science Applications, Pedigree, MESH: Cone-Rod Dystrophies, [SDV] Life Sciences [q-bio], Chemistry, Phenotype, Female, rod-cone dystrophy, Adult, MESH: Mutation, QH301-705.5, MESH: Pedigree, Genes, Recessive, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Phenotype, CCDC51, Catalysis, Article, Frameshift mutation, Inorganic Chemistry, Mitochondrial Proteins, 03 medical and health sciences, retinitis pigmentosa, Retinitis pigmentosa, medicine, Rod-cone dystrophy, Humans, Physical and Theoretical Chemistry, QD1-999, Molecular Biology, Gene, MESH: Genes, Recessive, MESH: Humans, Organic Chemistry, MITOK, candidate gene, MESH: Adult, medicine.disease, MESH: Male, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Female, Cone-Rod Dystrophies
Abstract

The purpose of this work was to identify the gene defect underlying a relatively mild rod-cone dystrophy (RCD), lacking disease-causing variants in known genes implicated in inherited retinal disorders (IRD), and provide transcriptomic and immunolocalization data to highlight the best candidate. The DNA of the female patient originating from a consanguineous family revealed no large duplication or deletion, but several large homozygous regions. In one of these, a homozygous frameshift variant, c.244_246delins17 p.(Trp82Valfs*4), predicted to lead to a nonfunctional protein, was identified in CCDC51. CCDC51 encodes the mitochondrial coiled-coil domain containing 51 protein, also called MITOK. MITOK ablation causes mitochondrial dysfunction. Here we show for the first time that CCDC51/MITOK localizes in the retina and more specifically in the inner segments of the photoreceptors, well known to contain mitochondria. Mitochondrial proteins have previously been implicated in IRD, although usually in association with syndromic disease, unlike our present case. Together, our findings add another ultra-rare mutation implicated in non-syndromic IRD, whose pathogenic mechanism in the retina needs to be further elucidated.

Published
2021
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8. First identification of ITM2B interactome in the human retina

Author

Christel Condroyer, Gilles Thuret, Isabelle Audo, Christelle Michiels, Christina Zeitz, Valérie Forster, Juliette Wohlschlegel, M. Argentini, Thibaut Léger, Zhiguo He, Camille Letellier, Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie, Ingénierie et Imagerie de la Greffe de Cornée (EA 2521, JE2521, IFR143), Université Jean Monnet [Saint-Étienne] (UJM), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Institut Jacques Monod (IJM (UMR_7592)), Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), Institute of Ophthalmology [London], University College of London [London] (UCL), Fondation de France, ANR-18-IAHU-0001, IHU FOReSIGHT, ANR-10-LABX-65, LABEX LIFESENSES, ANR-11-IDEX-0004-0, Agence Nationale de la Recherche, Retina France, UNADEV, [BR-GE-0619-0761-INSERM], Foundation Fighting Blindness grant, Gestionnaire, Hal Sorbonne Université, DES SENS POUR TOUTE LA VIE - - LIFESENSES2010 - ANR-10-LABX-0065 - LABX - VALID, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, Enabling Vision Restoration - - FOReSIGHT2018 - ANR-18-IAHU-0001 - IAHU - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Jean Monnet - Saint-Étienne (UJM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), ANR-10-LABX-0065,LIFESENSES,DES SENS POUR TOUTE LA VIE(2010), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), ANR-18-IAHU-0001,FOReSIGHT,Enabling Vision Restoration(2018), Biologie, Ingénierie et Imagerie pour l'Ophtalmologie (BIIO), and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)

Subjects
Male, Proteomics, Cerebellar Ataxia, Proteome, Science, [SDV]Life Sciences [q-bio], Quantitative proteomics, Neurophysiology, Biology, Interactome, Retina, Article, 03 medical and health sciences, 0302 clinical medicine, medicine, Missense mutation, Humans, Genetic Predisposition to Disease, Integral membrane protein, 030304 developmental biology, Adaptor Proteins, Signal Transducing, Aged, 80 and over, 0303 health sciences, Multidisciplinary, Amyloid beta-Peptides, Cerebellar ataxia, Mass spectrometry, Sequence Analysis, DNA, medicine.disease, Transmembrane protein, [SDV] Life Sciences [q-bio], HEK293 Cells, Mutation, Medicine, Dementia, Female, Cerebral amyloid angiopathy, Alzheimer's disease, medicine.symptom, Carrier Proteins, Neuroscience, 030217 neurology & neurosurgery, Protein Binding
Abstract

Integral Membrane Protein 2 B (ITM2B) is a type II ubiquitous transmembrane protein which role remains unclear. ITM2B mutations have been associated with different disorders: mutations leading to longer mutant proteins have been reported in two distinct Alzheimer-like autosomal dominant disorders with early-onset progressive dementia and cerebellar ataxia. Both disorders share neurological features including severe cerebral amyloid angiopathy, non-neuritic plaques, and fibrillary tangles as in Alzheimer disease. Our group reported a missense mutation in ITM2B, in an unusual retinal dystrophy with no dementia. This finding suggests a specific role of ITM2B in the retina. As the identification of retinal-specific ITM2B partners could bring new insights into the cellular functions of ITM2B, we performed quantitative proteomics of ITM2B interactome of the human retina. Overall, 457 ITM2B partners were identified with 8 of them involved in visual transduction. In addition, bulk Gene Ontology analyses showed that many ITM2B partners are involved in several other biological functions, such as microtubule organization, protein translation and interestingly, mitochondrial homeostasis. These data represent the first report of the ITM2B interactome in the human retina and may serve as a valuable inventory of new potential ITM2B partners for future investigations of ITM2B physiological functions and dysfunctions.

Published
2020
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9. DEEP PHENOTYPING AND FURTHER INSIGHTS INTO ITM2B-RELATED RETINAL DYSTROPHY

Author

Juliette Wohlschlegel, Christophe Habas, Marco Nassisi, Bingqian Liu, Christina Zeitz, Saddek Mohand-Said, José-Alain Sahel, Isabelle Audo, Anne Aubois, Christelle Michiels, and Camille Letellier

Subjects
0301 basic medicine, Male, Visual acuity, genetic structures, Nerve fiber layer, Visual Acuity, chemistry.chemical_compound, Mice, 0302 clinical medicine, In Situ Hybridization, medicine.diagnostic_test, Optical Imaging, General Medicine, Diabetic retinopathy, Middle Aged, medicine.anatomical_structure, Phenotype, Female, medicine.symptom, Tomography, Optical Coherence, medicine.medical_specialty, In situ hybridization, Retina, 03 medical and health sciences, Ophthalmology, Retinal Dystrophies, medicine, Electroretinography, Animals, Humans, RNA, Messenger, Outer nuclear layer, Adaptor Proteins, Signal Transducing, Aged, Retrospective Studies, business.industry, Retinal, medicine.disease, eye diseases, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, chemistry, Gene Expression Regulation, sense organs, business, 030217 neurology & neurosurgery
Abstract

PURPOSE To reappraise the presentation and the course of ITM2B-related retinal dystrophy and give further insights into ITM2B expression in the retina. METHODS The clinical data of nine subjects with ITM2B-related retinal dystrophy were retrospectively reviewed. The genetic mutation was assessed for its influence on splicing in cultured fibroblasts. The cellular expression of ITM2B within the inner retina was investigated in wild-type mice through mRNA in situ hybridization. RESULTS All patients complained of decreased vision and mild photophobia around their twenties-thirties. The peculiar feature was the hyperreflective material on optical coherence tomography within the inner retina and the central outer nuclear layer with thinning of the retinal nerve fiber layer. Although retinal imaging revealed very mild or no changes over the years, the visual acuity slowly decreased with about one Early Treatment Diabetic Retinopathy Study letter per year. Finally, full-field electroretinography showed a mildly progressive inner retinal and cone dysfunction. ITM2B mRNA is expressed in all cellular types of the inner retina. Disease mechanism most likely involves mutant protein misfolding and/or modified protein interaction rather than misplicing. CONCLUSION ITM2B-related retinal dystrophy is a peculiar, rare, slowly progressive retinal degeneration. Functional examinations (full-field electroretinography and visual acuity) seem more accurate in monitoring the progression in these patients because imaging tends to be stable over the years.

Published
2020

10. Impact of the COVID-19 lockdown on basic science research in ophthalmology: the experience of a highly specialized research facility in France

Author

José-Alain Sahel, Vasily Smirnov, Isabelle Audo, Juliette Wohlschlegel, Dominique Santiard-Baron, Serge Picaud, Christina Zeitz, Marco Nassisi, Juliette Varin, Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), DHU Sight Restore [Paris], Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), University College of London [London] (UCL), Fondation Ophtalmologique Adolphe de Rothschild [Paris], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Académie des Sciences, Institut de France, This work was performed in the frame of the grant IHU FOReSIGHT [ANR-18-IAHU-0001] supported by French state funds managed by the Agence Nationale de la Recherche within the Investissements d'Avenir program., ANR-18-IAHU-0001,FOReSIGHT,Enabling Vision Restoration(2018), Bodescot, Myriam, Enabling Vision Restoration - - FOReSIGHT2018 - ANR-18-IAHU-0001 - IAHU - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre d'investigation clinique Quinze-Vingts [CHNO] (CIC1423 - CIC QUINZE-VINGTS), Institut Hospitalo-Universitaire FOReSIGHT, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO)-Sorbonne Université (SU), and Académie des Sciences [Paris]

Subjects
2019-20 coronavirus outbreak, Biomedical Research, Scientific community, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Pneumonia, Viral, MEDLINE, Betacoronavirus, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, 030212 general & internal medicine, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Workplace, Pandemics, ComputingMilieux_MISCELLANEOUS, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, biology, SARS-CoV-2, business.industry, Comment, Academies and Institutes, COVID-19, medicine.disease, biology.organism_classification, Ophthalmology, Pneumonia, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 030221 ophthalmology & optometry, France, Medical emergency, Visual system, Coronavirus Infections, business
Abstract

International audience; no abstract

Published
2020
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11. Prevalence of ABCA4 Deep-Intronic Variants and Related Phenotype in An Unsolved 'One-Hit' Cohort with Stargardt Disease

Author

Christel Condroyer, Juliette Wohlschlegel, Juliette Varin, Aline Antonio, Claire-Marie Dhaenens, Cécile Méjécase, Christina Zeitz, José-Alain Sahel, Isabelle Audo, Saddek Mohand-Said, Camille Andrieu, Marco Nassisi, CHU Lille, Inserm, Université de Lille, Centre d'investigation clinique Quinze-Vingts [CHNO] [CIC1423 - CIC QUINZE-VINGTS], Institut de la Vision, Lille Neurosciences & Cognition (LilNCog) - U 1172, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Académie des Sciences [Paris], Institut de France, University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), University College of London [London] (UCL), ANR-18-IAHU-0001,FOReSIGHT,Enabling Vision Restoration(2018), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, and Académie des Sciences

Subjects
0301 basic medicine, abca4, Male, ABCA4, lcsh:Chemistry, 0302 clinical medicine, Gene Frequency, Genotype, Prevalence, lcsh:QH301-705.5, Spectroscopy, Genetics, Sanger sequencing, biology, Stargardt disease, genotype-phenotype correlation, deep-intronic variants, General Medicine, Middle Aged, 3. Good health, Computer Science Applications, Phenotype, symbols, Female, France, Adult, Locus (genetics), Catalysis, Article, Inorganic Chemistry, 03 medical and health sciences, symbols.namesake, Young Adult, medicine, Humans, Computer Simulation, Genetic Predisposition to Disease, Physical and Theoretical Chemistry, Allele, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Molecular Biology, Genetic Association Studies, Aged, Retrospective Studies, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Organic Chemistry, Intron, Sequence Analysis, DNA, medicine.disease, Introns, Minor allele frequency, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, lcsh:Biology (General), lcsh:QD1-999, Mutation, 030221 ophthalmology & optometry, biology.protein, ATP-Binding Cassette Transporters
Abstract

We investigated the prevalence of reported deep-intronic variants in a French cohort of 70 patients with Stargardt disease harboring a monoallelic pathogenic variant on the exonic regions of ABCA4. Direct Sanger sequencing of selected intronic regions of ABCA4 was conducted. Complete phenotypic analysis and correlation with the genotype was performed in case a known intronic pathogenic variant was identified. All other variants found on the analyzed sequences were queried for minor allele frequency and possible pathogenicity by in silico predictions. The second mutated allele was found in 14 (20%) subjects. The three known deep-intronic variants found were c.5196+1137G&gt, A in intron 36 (6 subjects), c.4539+2064C&gt, T in intron 30 (4 subjects) and c.4253+43G&gt, A in intron 28 (4 subjects). Even though the phenotype depends on the compound effect of the biallelic variants, a genotype-phenotype correlation suggests that the c.5196+1137G&gt, A was mostly associated with a mild phenotype and the c.4539+2064C&gt, T with a more severe one. A variable effect was instead associated with the variant c.4253+43G&gt, A. In addition, two novel variants, c.768+508A&gt, G and c.859-245_859-243delinsTGA never associated with Stargardt disease before, were identified and a possible splice defect was predicted in silico. Our study calls for a larger cohort analysis including targeted locus sequencing and 3D protein modeling to better understand phenotype-genotype correlations associated with deep-intronic changes and patients&rsquo, selection for clinical trials.

Published
2019
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