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1. POLR1B and neural crest cell anomalies in Treacher Collins syndrome type 4

Author

Sanchez, Elodie, Laplace-Builhé, Béryl, Mau-Them, Frédéric Tran, Richard, Eric, Goldenberg, Alice, Toler, Tomi L., Guignard, Thomas, Gatinois, Vincent, Vincent, Marie, Blanchet, Catherine, Boland, Anne, Bihoreau, Marie Thérèse, Deleuze, Jean-Francois, Olaso, Robert, Nephi, Walton, Lüdecke, Hermann-Josef, Verheij, Joke B. G. M., Moreau-Lenoir, Florence, Denoyelle, Françoise, Rivière, Jean-Baptiste, Laplanche, Jean-Louis, Willing, Marcia, Captier, Guillaume, Apparailly, Florence, Wieczorek, Dagmar, Collet, Corinne, Djouad, Farida, Geneviève, David, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Biopathologie [CHRU Montpellier], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Groupe d'Études et de Recherche Interdisciplinaire en Information et COmmunication - ULR 4073 (GERIICO ), Université de Lille, CHU Montpellier, Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Service ORL [Hôpital Gui de Chauliac] (CHRU de Montpellier), Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Fondation Jean Dausset CEPH, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], University of Groningen [Groningen], Centre Hospitalier Eure-Seine - Hôpital d'Evreux - Vernon (Evreux), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris-Saclay, Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département Chirurgie Pédiatrique [CHRU Montpellier], Pôle Femme Mère Enfant [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, Service d'ORL, Hôpital Gui de Chauliac (CHRU de Montpellier), Service d'ORL pédiatrique et Chirurgie Cervico-faciale [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Salvy-Córdoba, Nathalie, Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB)

Subjects
Treacher Collins-Franceschetti, [SDV.GEN] Life Sciences [q-bio]/Genetics, Article, Craniofacial Abnormalities, DYSOSTOSIS, Cell Movement, Treacher Collins–Franceschetti, Exome Sequencing, COLLINSSYNDROME,TREACHER, Animals, Humans, Genetic Predisposition to Disease, Zebrafish, TOOLS, neural crest cells, P53, [SDV.GEN]Life Sciences [q-bio]/Genetics, fungi, POLR1B, apoptosis, Nuclear Proteins, Cell Differentiation, DNA-Directed RNA Polymerases, Phosphoproteins, Neural Crest, Mutation, embryonic structures, TCOF1 GENE-PRODUCT, Tumor Suppressor Protein p53, RIBOSOMAL-RNA, Mandibulofacial Dysostosis
Abstract

PURPOSE: Treacher Collins syndrome (TCS) is a rare autosomal dominant mandibulofacial dysostosis, with a prevalence of 0.2-1/10,000. Features include bilateral and symmetrical malar and mandibular hypoplasia and facial abnormalities due to abnormal neural crest cell (NCC) migration and differentiation. To date, three genes have been identified: TCOF1, POLR1C, and POLR1D. Despite a large number of patients with a molecular diagnosis, some remain without a known genetic anomaly. METHODS: We performed exome sequencing for four individuals with TCS but who were negative for pathogenic variants in the known causative genes. The effect of the pathogenic variants was investigated in zebrafish. RESULTS: We identified three novel pathogenic variants in POLR1B. Knockdown of polr1b in zebrafish induced an abnormal craniofacial phenotype mimicking TCS that was associated with altered ribosomal gene expression, massive p53-associated cellular apoptosis in the neuroepithelium, and reduced number of NCC derivatives. CONCLUSION: Pathogenic variants in the RNA polymerase I subunit POLR1B might induce massive p53-dependent apoptosis in a restricted neuroepithelium area, altering NCC migration and causing cranioskeletal malformations. We identify POLR1B as a new causative gene responsible for a novel TCS syndrome (TCS4) and establish a novel experimental model in zebrafish to study POLR1B-related TCS. ispartof: GENETICS IN MEDICINE vol:22 issue:3 pages:547-556 ispartof: location:United States status: published

Published
2020

2. The effect of PTC124 on choroideremia fibroblasts and iPSC-derived RPE raises considerations for therapy

Author

Valerie De Luca, David Baux, Vasiliki Kalatzis, Nicolas Cereso, Simona Torriano, Anne-Françoise Roux, Christian P. Hamel, Isabelle Meunier, Nejla Erkilic, Mariya Moosajee, Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Montpellier (UM), Service d'Ophtalmologie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Guy de Chauliac, Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Department of Ophthalmology [London, UK], Great Ormond Street Hospital for Children [London] (GOSH), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), roussel, pascale, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), IFR3, and Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Induced Pluripotent Stem Cells, lcsh:Medicine, Retinal Pigment Epithelium, Biology, Article, Choroideremia, 03 medical and health sciences, chemistry.chemical_compound, medicine, Humans, Induced pluripotent stem cell, lcsh:Science, Zebrafish, Cells, Cultured, Oxadiazoles, Multidisciplinary, Retinal pigment epithelium, lcsh:R, Retinal, Fibroblasts, medicine.disease, biology.organism_classification, Stop codon, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, chemistry, Proteasome inhibitor, Cancer research, lcsh:Q, Retinal Dystrophies, medicine.drug
Abstract

Inherited retinal dystrophies (IRDs) are caused by mutations in over 200 genes, resulting in a range of therapeutic options. Translational read-through inducing drugs (TRIDs) offer the possibility of treating multiple IRDs regardless of the causative gene. TRIDs promote ribosomal misreading of premature stop codons, which results in the incorporation of a near-cognate amino acid to produce a full-length protein. The IRD choroideremia (CHM) is a pertinent candidate for TRID therapy, as nonsense variants cause 30% of cases. Recently, treatment of the UAA nonsense-carrying CHM zebrafish model with the TRID PTC124 corrected the underlying biochemical defect and improved retinal phenotype. To be clinically relevant, we studied PTC124 efficiency in UAA nonsense-carrying human fibroblasts and induced pluripotent stem cell-derived retinal pigment epithelium, as well as in a UAA-mutated CHM overexpression system. We showed that PTC124 treatment induces a non-significant trend for functional rescue, which could not be improved by nonsense-mediated decay inhibition. Furthermore, it does not produce a detectable CHM-encoded protein even when coupled with a proteasome inhibitor. We suggest that drug efficiency may depend upon on the target amino acid and its evolutionary conservation, and argue that patient cells should be screened in vitro prior to inclusion in a clinical trial.

Published
2018

3. The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management

Author

Oliver Bartsch, Nanna Dahl Rendtorff, Toke Bek, Julia Doll, Karen Østergaard, Béatrice Bocquet, Katherine Harrop-Griffiths, Shamima Rahman, Wojciech Kopec, Sture Lindholm, Claes Möller, Himanshu Khandelia, Kaukab Rajput, Barbara Vona, Cécile Delettre, Hanne Jensen, Lucinda Carr, Louise C. Wilson, Hanne Poulsen, Michael Bille, Maria Bitner-Glindzicz, Tobias Moser, Linda M. Luxon, Lisbeth Tranebjærg, Thomas Haaf, Troels Lyngbye, Nicola Strenzke, Hendrik Rosewich, Christian P. Hamel, Hanne H Owen, Tony Sirimanna, Department of Audiology, H:S Bispebjerg Hospital, Department of Cellular and Molecular Medicine [Copenhagen], Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), InnerEarLab, Dept. of Otolaryngology, Department of Animal Science, Aarhus University [Aarhus], Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, Université de Montpellier (UM), and Great Ormond Street Hospital for Children [London] (GOSH)

Subjects
Male, 0301 basic medicine, [SDV]Life Sciences [q-bio], Denmark, Auditory neuropathy, Sensorineural, Congenital, 0302 clinical medicine, Foot Deformities, Congenital/epidemiology, Germany, ATP1A3, Missense mutation, Hearing Loss, Central, Reflex, Abnormal/genetics, Child, Central, Genetics (clinical), Hearing Loss, Sensorineural/epidemiology, Optic Atrophy/epidemiology, Phenotype, Mutation, Missense/genetics, Child, Preschool, Mutation (genetic algorithm), Female, Sodium-Potassium-Exchanging ATPase, medicine.symptom, Foot Deformities, Adult, medicine.medical_specialty, Pes cavus, Hearing Loss, Central/epidemiology, Adolescent, Cerebellar Ataxia, Foot Deformities, Congenital, Hearing loss, Hearing Loss, Sensorineural, Germany/epidemiology, Mutation, Missense, Molecular Dynamics Simulation, Biology, Young Adult, 03 medical and health sciences, Atrophy, Internal medicine, Reflex, Journal Article, otorhinolaryngologic diseases, Genetics, medicine, Humans, Na+/K+-ATPase, Preschool, Hearing Loss, Retrospective Studies, Sweden, Reflex, Abnormal, Cerebellar ataxia, Cerebellar Ataxia/epidemiology, Sodium-Potassium-Exchanging ATPase/chemistry, medicine.disease, Denmark/epidemiology, body regions, Optic Atrophy, Sweden/epidemiology, 030104 developmental biology, Endocrinology, Mutation, Abnormal, Missense, Function (biology), 030217 neurology & neurosurgery
Abstract

International audience; Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing impairment (CAPOS) is a rare clinically distinct syndrome caused by a single dominant missense mutation, c.2452G\textgreaterA, p.Glu818Lys, in ATP1A3, encoding the neuron-specific alpha subunit of the Na+/K+-ATPase α3. Allelic mutations cause the neurological diseases rapid dystonia Parkinsonism and alternating hemiplegia of childhood, disorders which do not encompass hearing or visual impairment. We present detailed clinical phenotypic information in 18 genetically confirmed patients from 11 families (10 previously unreported) from Denmark, Sweden, UK and Germany indicating a specific type of hearing impairment-auditory neuropathy (AN). All patients were clinically suspected of CAPOS and had hearing problems. In this retrospective analysis of audiological data, we show for the first time that cochlear outer hair cell activity was preserved as shown by the presence of otoacoustic emissions and cochlear microphonic potentials, but the auditory brainstem responses were grossly abnormal, likely reflecting neural dyssynchrony. Poor speech perception was observed, especially in noise, which was beyond the hearing level obtained in the pure tone audiograms in several of the patients presented here. Molecular modelling and in vitro electrophysiological studies of the specific CAPOS mutation were performed. Heterologous expression studies of α3 with the p.Glu818Lys mutation affects sodium binding to, and release from, the sodium-specific site in the pump, the third ion-binding site. Molecular dynamics simulations confirm that the structure of the C-terminal region is affected. In conclusion, we demonstrate for the first time evidence for auditory neuropathy in CAPOS syndrome, which may reflect impaired propagation of electrical impulses along the spiral ganglion neurons. This has implications for diagnosis and patient management. Auditory neuropathy is difficult to treat with conventional hearing aids, but preliminary improvement in speech perception in some patients~suggests that cochlear implantation may be effective~in CAPOS patients.

Published
2018

4. WFS1 in Optic Neuropathies: Mutation Findings in Nonsyndromic Optic Atrophy and Assessment of Clinical Severity

Author

Joanna Grenier, Corinne Baudoin, Christian P. Hamel, François Halloy, Isabelle Meunier, Béatrice Bocquet, Agathe Roubertie, Etienne Esmenjaud, Guy Lenaers, Vincent Daien, Cécile Delettre, Catherine Blanchet, Service d'Ophtalmologie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Guy de Chauliac, Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, Male, Retinal Ganglion Cells, 0301 basic medicine, medicine.medical_specialty, Visual acuity, Adolescent, genetic structures, Wolfram syndrome, Hearing loss, Visual impairment, Visual Acuity, Nerve fiber layer, Audiology, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, Nerve Fibers, 0302 clinical medicine, Atrophy, Diabetes mellitus, Ophthalmology, Humans, Medicine, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Child, Retrospective Studies, business.industry, Membrane Proteins, Retinal, Middle Aged, medicine.disease, eye diseases, 3. Good health, Optic Atrophy, 030104 developmental biology, medicine.anatomical_structure, chemistry, Mutation, 030221 ophthalmology & optometry, Female, sense organs, medicine.symptom, business
Abstract

Purpose To search for WFS1 mutations in patients with optic atrophy (OA) and assess visual impairment. Design Retrospective molecular genetic and clinical study. Participants Patients with OA followed at a national referral center specialized in genetic sensory diseases. Methods Mutation screening in WFS1 was performed by Sanger sequencing. WFS1 -positive patients were evaluated on visual acuity (VA) and retinal nerve fiber layer (RNFL) thickness using time-domain (TD) or spectral-domain (SD) optical coherence tomography (OCT). Statistical analysis was performed. Main Outcome Measures Mutation identification, VA values, and RNFL thickness in sectors. Results Biallelic WFS1 mutations were found in 3 of 24 unrelated patients (15%) with autosomal recessive nonsyndromic optic atrophy (arNSOA) and in 8 patients with autosomal recessive Wolfram syndrome (arWS) associated with diabetes mellitus and OA. Heterozygous mutations were found in 4 of 20 unrelated patients (20%) with autosomal dominant OA. The 4 WFS1 -mutated patients of this latter group with hearing loss were diagnosed with autosomal dominant Wolfram-like syndrome (adWLS). Most patients had VA decrease, with logarithm of the minimum angle of resolution (logMAR) values lower in arWS than in arNSOA (1.530 vs. 0.440; P = 0.026) or adWLS (0.240; P = 0.006) but not differing between arNSOA and adWLS ( P = 0.879). All patients had decreased RNFL thickness that was worse in arWS than in arNSOA (SD OCT, 35.50 vs. 53.80 μm; P = 0.018) or adWLS (TD-OCT, 45.84 vs. 59.33 μm; P = 0.049). The greatest difference was found in the inferior bundle. Visual acuity was negatively correlated with RNFL thickness ( r = −0.89; P = 0.003 in SD OCT and r = −0.75; P = 0.01 in TD-OCT). Conclusions WFS1 is a gene causing arNSOA. Patients with this condition had significantly less visual impairment than those with arWS. Thus systematic screening of WFS1 must be performed in isolated, sporadic, or familial optic atrophies.

Published
2016

5. Dietary, environmental, and genetic risk factors of Extensive Macular Atrophy with Pseudodrusen, a severe bilateral macular atrophy of middle-aged patients

Author

Carl Arndt, Elsa Jozefowicz, Saddek Mohand Said, Béatrice Bocquet, Benjamin Wolff, Eric H Souied, Christian P. Hamel, Cécile Delcourt, F. Devin, Bernard Puech, M. Quaranta, Isabelle Meunier, Thibault Mura, Marie-Christine Picot, Xavier Zanlonghi, Catherine Creuzot-Garcher, José-Alain Sahel, Dominique Deplanque, Solange Milazzo, Olivia Zambrowski, Isabelle Audo, Vasiliki Kalatzis, Nour Al Dain Marzouka, Rocio Blanco Garavito, Sophie Arsène, Hassiba Oubraham, Corinne Baudoin, Pierre Gastaud, Sabine Defoort-Dhellemmes, Sarah Perez-Roustit, Annie Lacroux, Aymeric Douillard, Isabelle Drumare, Martine Mauget-Faÿsse, Valérie Gissot, Salomon Y. Cohen, CIC Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Lille, Centre Hospitalier Universitaire de Reims (CHU Reims), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Centre d'Investigation Clinique - Innovation Technologique de Lille - CIC 1403 - CIC 9301 (CIC Lille), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHI Créteil, Service d'Ophtalmologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), 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 Intercommunal de Créteil (CHIC), CHU Amiens-Picardie, Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), The French Ministry of Health., Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Meunier, Isabelle

Subjects
0301 basic medicine, Male, Organes des sens, genetic structures, Mediterranean, Diet, Mediterranean, 0302 clinical medicine, Risk Factors, Prospective Studies, Prospective cohort study, Multidisciplinary, Incidence (epidemiology), Environmental exposure, Middle Aged, macular degeneration, retinal diseases, 3. Good health, Medicine, Female, France, Adult, medicine.medical_specialty, Science, Sensory Organs, Médecine humaine et pathologie, Retinal Drusen, Article, 03 medical and health sciences, Complement pathway regulation, Internal medicine, Geographic Atrophy, medicine, Humans, Genetic Predisposition to Disease, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Retrospective Studies, Aged, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, business.industry, Case-control study, Retrospective cohort study, dégénérescence maculaire, Feeding Behavior, Environmental Exposure, medicine.disease, eye diseases, Diet, 030104 developmental biology, Case-Control Studies, 030221 ophthalmology & optometry, Maculopathy, Human health and pathology, degénération rétinienne, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, sense organs, Age of onset, business
Abstract

EMAP (Extensive Macular Atrophy with Pseudodrusen) is a maculopathy we recently described that shares pseudodrusen and geographic atrophy with Age-related Macular Disease (AMD). EMAP differs from AMD by an earlier age of onset (50-55 years) and a characteristic natural history comprising a night blindness followed by a severe visual loss. In a prospective case-control study, ten referral centers included 115 EMAP (70 women, 45 men) patients and 345 matched controls to appraise dietary, environmental, and genetic risk factors. The incidence of EMAP (mean 2.95/1.106) was lower in Provence-Côte d’Azur with a Mediterranean diet (1.9/1.106), and higher in regions with intensive farming or industrialized activities (5 to 20/1.106). EMAP patients reported toxic exposure during professional activities (OR 2.29). The frequencies of common AMD complement factor risk alleles were comparable in EMAP. By contrast, only one EMAP patient had a rare AMD variant. This study suggests that EMAP could be a neurodegenerative disorder caused by lifelong toxic exposure and that it is associated with a chronic inflammation and abnormal complement pathway regulation. This leads to diffuse subretinal deposits with rod dysfunction and cone apoptosis around the age of 50 with characteristic extensive macular atrophy and paving stones in the far peripheral retina.

Published
2018

6. Identification of Inherited Retinal Disease-Associated Genetic Variants in 11 Candidate Genes

Author

Lonneke Haer-Wigman, Chris F. Inglehearn, L. Ingeborgh van den Born, Manir Ali, Susanne Roosing, M Imran Khan, Frans P.M. Cremers, Graeme C.M. Black, Galuh D.N. Astuti, Carmel Toomes, Béatrice Bocquet, Carel B. Hoyng, Martin McKibbin, Mathieu Quinodoz, Gaël Manes, Mohammed E El-Asrag, Christian P. Hamel, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Montpellier (UM), Service d'Ophtalmologie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Guy de Chauliac, Centre de référence des affections sensorielles d'origine génétique, and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac

Subjects
0301 basic medicine, Candidate gene, lcsh:QH426-470, inherited retinal diseases, [SDV]Life Sciences [q-bio], Biology, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Article, whole exome sequencing, candidate retinal disease genes, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Inherited retinal diseases, parasitic diseases, Genetics, Exome, Gene, Genetics (clinical), Exome sequencing, Candidate retinal disease genes, Genetic heterogeneity, Whole exome sequencing, Disease gene identification, Minor allele frequency, lcsh:Genetics, 030104 developmental biology, Small nuclear ribonucleoprotein
Abstract

Inherited retinal diseases (IRDs) display an enormous genetic heterogeneity. Whole exome sequencing (WES) recently identified genes that were mutated in a small proportion of IRD cases. Consequently, finding a second case or family carrying pathogenic variants in the same candidate gene often is challenging. In this study, we searched for novel candidate IRD gene-associated variants in isolated IRD families, assessed their causality, and searched for novel genotype-phenotype correlations. Whole exome sequencing was performed in 11 probands affected with IRDs. Homozygosity mapping data was available for five cases. Variants with minor allele frequencies ≤ 0.5% in public databases were selected as candidate disease-causing variants. These variants were ranked based on their: (a) presence in a gene that was previously implicated in IRD; (b) minor allele frequency in the Exome Aggregation Consortium database (ExAC); (c) in silico pathogenicity assessment using the combined annotation dependent depletion (CADD) score; and (d) interaction of the corresponding protein with known IRD-associated proteins. Twelve unique variants were found in 11 different genes in 11 IRD probands. Novel autosomal recessive and dominant inheritance patterns were found for variants in Small Nuclear Ribonucleoprotein U5 Subunit 200 ( javax.xml.bind.JAXBElement@ccb913c ) and Zinc Finger Protein 513 ( javax.xml.bind.JAXBElement@1d5964bc ), respectively. Using our pathogenicity assessment, a variant in DEAH-Box Helicase 32 ( javax.xml.bind.JAXBElement@7e33d494 ) was the top ranked novel candidate gene to be associated with IRDs, followed by eight medium and lower ranked candidate genes. The identification of candidate disease-associated sequence variants in 11 single families underscores the notion that the previously identified IRD-associated genes collectively carry > 90% of the defects implicated in IRDs. To identify multiple patients or families with variants in the same gene and thereby provide extra proof for pathogenicity, worldwide data sharing is needed.

Published
2018

7. WholeUSH2AGene Sequencing Identifies Several New Deep Intronic Mutations

Author

Mireille Claustres, Christel Vaché, Catherine Blanchet, Sue Malcolm, Alessandro Liquori, David Baux, Anne-Françoise Roux, Christian P. Hamel, Michel Koenig, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), University College of London [London] (UCL), IFR3, and Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, 0301 basic medicine, pseudoexon, Morpholino, RNA Splicing, DNA Mutational Analysis, Molecular Sequence Data, Gene Expression, whole gene sequencing, Biology, medicine.disease_cause, DNA sequencing, Morpholinos, 03 medical and health sciences, Exon, USH2A, deep intronic mutation, Genetics, medicine, Humans, RNA, Messenger, Gene, Genetics (clinical), [SDV.GEN]Life Sciences [q-bio]/Genetics, Extracellular Matrix Proteins, Mutation, Base Sequence, Intron, Computational Biology, High-Throughput Nucleotide Sequencing, Exons, Oligonucleotides, Antisense, Introns, Pedigree, 030104 developmental biology, minigene assays, NGS, RNA splicing, Female, sequence capture, Usher Syndromes, HeLa Cells, Minigene
Abstract

International audience; Deep intronic mutations leading to pseudoexon (PE) insertions are underestimated and most of these splicing alterations have been identified by transcript analysis, for instance, the first deep intronic mutation in USH2A, the gene most frequently involved in Usher syndrome type II (USH2). Unfortunately, analyzing USH2A transcripts is challenging and for 1.8%-19% of USH2 individuals carrying a single USH2A recessive mutation, a second mutation is yet to be identified. We have developed and validated a DNA next-generation sequencing approach to identify deep intronic variants in USH2A and evaluated their consequences on splicing. Three distinct novel deep intronic mutations have been identified. All were predicted to affect splicing and resulted in the insertion of PEs, as shown by minigene assays. We present a new and attractive strategy to identify deep intronic mutations, when RNA analyses are not possible. Moreover, the bioinformatics pipeline developed is independent of the gene size, implying the possible application of this approach to any disease-linked gene. Finally, an antisense morpholino oligonucleotide tested in vitro for its ability to restore splicing caused by the c.9959-4159A>G mutation provided high inhibition rates, which are indicative of its potential for molecular therapy.

Published
2015

8. Five-Year Hearing Outcomes in Bilateral Simultaneously Cochlear-Implanted Adult Patients

Author

Olivier Deguine, Antoine Vanier, Evelyne Ferrary, Benoit Godey, Yann Nguyen, Olivier Sterkers, Jean-Pierre Bebear, Alain Robier, Michel Mondain, Daniele De Seta, Isabelle Mosnier, Service d'Oto-Rhino-Laryngologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité d’Otologie, implants auditifs et chirurgie de la base du crâne [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Réhabilitation Chirurgicale mini-Invasive et Robotisée de l'Audition, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), PSIGIAM, Institut National de la Santé et de la Recherche Médicale (INSERM), Biostatistique, Pharmacoépidémiologie et Mesures Subjectives en Santé, PRES Université Nantes Angers Le Mans (UNAM), Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service d'ORL et de chirurgie maxillo-faciale [Rennes] = ENT Head and Neck Surgery [Rennes], CHU Pontchaillou [Rennes], Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service ORL et chirurgie cervico-faciale [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, Centre de recherche cerveau et cognition (CERCO), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Service d'oto-rhino-laryngologie et d'oto-neurologie, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Equipe Medicis, Ltsi, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Service ORL, otoneurologie et ORL pédiatrique [CHU Toulouse], Pôle Céphalique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J), and Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, medicine.medical_treatment, Audiology, Deafness, Signal-To-Noise Ratio, long-term results, 01 natural sciences, speech perception, localization, 0302 clinical medicine, Hearing, Cochlear implant, Prospective Studies, Young adult, 030223 otorhinolaryngology, Prospective cohort study, 010301 acoustics, Hearing Tests, Middle Aged, Cochlear Implantation, bilateral implantation, cochlear implant, otorhinolaryngology2734 pathology and forensic medicine, physiology, sensory systems, 3616, Treatment Outcome, QUIET, Female, [SDV.IB]Life Sciences [q-bio]/Bioengineering, medicine.symptom, Sound localization, Adult, medicine.medical_specialty, Speech perception, Hearing loss, Hearing Loss, Bilateral, 03 medical and health sciences, Speech and Hearing, Young Adult, 0103 physical sciences, medicine, otorhinolaryngologic diseases, Humans, Sound Localization, Aged, [SDV.IB] Life Sciences [q-bio]/Bioengineering, business.industry, Noise, Cochlear Implants, Otorhinolaryngology, business
Abstract

Objective: To report the speech performance and sound localization in adult patients 5 years after bilateral simultaneous cochlear implantation and to evaluate the change in speech scores between 1 and 5 years. Design: In this prospective multicenter study, 26 patients were evaluated 5 years after implantation using long straight electrode arrays (MED-EL Combi 40+, standard electrode array, 31 mm). Speech perception was measured using disyllabic words in quiet and noise, with the speech coming from the front and a cocktail party background noise coming from 5 loudspeakers. Speech localization measurements were performed in noise under the same test conditions. These results were compared to those obtained at 1 year reported in a previous study. Results: Five years after implantation, an improvement in speech performance scores compared to 1 year after implantation was found for the poorer ear both in quiet and in noise (+12.1 ± 2.6%, p < 0.001). The lower the speech score of the poorer ear at 1 year, the greater the improvement at 5 years, both in quiet (r = -0.62) and at a signal-to-noise ratio of +15 dB (r = -0.58). The sound localization on the horizontal plane in noise provided by bilateral implantation was better than the unilateral one and remained stable after the results observed at 1 year. Conclusion: In adult patients simultaneously and bilaterally implanted, the poorest speech scores improved between 1 and 5 years after implantation. These findings are an additional element to recommend bilateral implantation in adult patients. The use of both cochlear implants and speech training sessions for patients with poor performance should continue in the period after 1 year following implantation, since the speech scores will improve over time.

Published
2016

9. De novo 15q21.1q21.2 deletion identified through FBN1 MLPA and refined by 244K array-CGH in a female teenager with incomplete Marfan syndrome

Author

Guillaume Jondeau, Nathalie Ruiz-Pallares, Jean-Damien Metaizeau, Christel Thauvin-Robinet, Frédéric Huet, Francine Mugneret, Fanny Coron, Bruno Leheup, Catherine Boileau, Edith Durand, Patrick Callier, Laurence Faivre, Philippe Khau Van Kien, Aurélie Plancke, Jean-Eric Wolf, Samuel Bidot, Delphine Minot, Corinne Baudoin, Véronique Dulieu, Mireille Claustres, Génétique des Anomalies du Développement (GAD), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire de cytogénétique (CHU de Dijon), Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, Service de Cardiologie [CHU de Dijon], Pôle Rééducation - Réadaptation (Médecine Physique et Réadaptation) (CHU de Dijon), Service orthopédie - traumatologie [CHU de Dijon], Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'Ophtalmologie (CHU de Dijon), Centre de référence MARFAN, Hôpital Bichat, Génétique, chromosome et cancer, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Service de Pédiatrie, and CHU Dijon

Subjects
Adult, Male, musculoskeletal diseases, Proband, Marfan syndrome, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, [SDV]Life Sciences [q-bio], Fibrillin-1, Biology, Fibrillins, Bioinformatics, Polymerase Chain Reaction, Marfan Syndrome, Loss of heterozygosity, 03 medical and health sciences, Transforming Growth Factor beta, Intellectual Disability, Genetics, medicine, Humans, Multiplex ligation-dependent probe amplification, Allele, Child, Gene, In Situ Hybridization, Fluorescence, Genetics (clinical), Oligonucleotide Array Sequence Analysis, Sequence Deletion, 030304 developmental biology, Chromosomes, Human, Pair 15, Comparative Genomic Hybridization, 0303 health sciences, Microfilament Proteins, 030305 genetics & heredity, General Medicine, medicine.disease, Pedigree, 3. Good health, Phenotype, Mutation, Microsatellite, Female, DNA Probes, Haploinsufficiency, Microsatellite Repeats
Abstract

International audience; Interstitial deletions involving the 15q21.1 band are very rare. Only 4 of these cases have been studied using molecular cytogenetic techniques in order to confirm the deletion of the whole FBN1 gene. The presence of clinical features of the Marfan syndrome (MFS) spectrum associated with mental retardation has been described in only 2/4 patients. Here we report on a 16-year-old female referred for suspicion of MFS (positive thumb and wrist sign, scoliosis, joint hyperlaxity, high-arched palate with dental crowding, dysmorphism, mitral insufficiency with dystrophic valve, striae). She had therefore 3 minor criteria according to the Ghent nosology. She also had speech disabilities but could follow normal school training. Direct sequencing of the FBN1, TGFBR1 and TGFBR2 genes was negative. MLPA revealed a genomic deletion of the whole FBN1 gene, confirmed by loss of heterozygosity of maternal alleles for several microsatellite markers surrounding the FBN1 gene. The deletion was confirmed by FISH using a FBN1 probe and was not found in the parents. Array-CGH permitted to define a 2.97 Mb deletion, which was the smallest 15q microdeletion including FBN1. Contrary to the other published observations, our proband does not exhibit mental retardation, but neuropsychological evaluations revealed an attention deficit as well as a deficit in information-processing speed. Haploinsufficiency of FBN1 is likely to contribute to the presence of MFS features. However, attenuated features could be explained because disturbances of TGF-beta signalling associated with FBN1 mutations do not exert full phenotypic effect through simple haploinsufficiency. Phenotypic variability in other patients with interstitial deletions including 15q21.1 band may reflect differences in deletion size and/or cys/trans modifying factors.

Published
2010

10. Should transcobalamin deficiency be treated aggressively?

Author

Stuart J. Moat, Sylvie Odent, Guy Touati, Stéphane Giraudier, Ghislaine Bard, Graham Shortland, Manuel Schiff, Hélène Ogier de Baulny, Christian P. Hamel, Vincent Barlogis, De Villemeur, Hervé, Centre de référence des Maladies Métaboliques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Réanimation et Pédiatrie Néonatales, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Centre de référence Maladies Métaboliques, Laboratoire d'hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'hématologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, Department of Medical Biochemistry and Immunology, University Hospital of Wales (UHW), Centre de référence des anomalies du développement d'origine génétique, Department of Paediatrics, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and University Hospital of Wales

Subjects
medicine.medical_specialty, Anemia, Megaloblastic, Homocysteine, Anemia, DNA Mutational Analysis, Methylmalonic acid, [SDV.GEN] Life Sciences [q-bio]/Genetics, Polymerase Chain Reaction, Cobalamin, 03 medical and health sciences, chemistry.chemical_compound, Methionine, 0302 clinical medicine, Transcobalamin, Internal medicine, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Genetics, medicine, Humans, Megaloblastic anemia, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Genetics (clinical), DNA Primers, 030304 developmental biology, Transcobalamins, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, business.industry, Infant, Newborn, Infant, Biological Transport, medicine.disease, Pancytopenia, Protein Structure, Tertiary, 3. Good health, Endocrinology, chemistry, Mutation, Failure to thrive, Female, medicine.symptom, business, 030217 neurology & neurosurgery, Methylmalonic Acid
Abstract

International audience; Transcobalamin (transcobalamin II, TC) transports plasma vitamin B(12) (cobalamin, Cbl) into cells. TC deficiency is a rare autosomal recessive disorder causing intracellular Cbl depletion, which in turn causes megaloblastic bone marrow failure, accumulation of homocysteine and methylmalonic acid, and methionine depletion. The clinical presentation reflects intracellular Cbl defects, with early-onset failure to thrive with gastrointestinal symptoms, pancytopenia, and megaloblastic anemia, sometimes followed by neurological complications. We report the clinical, biological, and molecular findings and the outcome in five TC-deficient patients. The three treated early had an initial favorable outcome, whereas the two treated inadequately had late-onset severe neuro-ophthalmological impairment. Even if the natural course of the disease over time might also result in late-onset symptoms in the aggressively treated patients, these data emphasize that TC deficiency is a severe disorder requiring early detection and probably long-term aggressive therapy. Mutation analysis revealed six unreported mutations in the TCN2 gene. In silico structural analysis showed that these mutations disrupt the Cbl-TC interaction domain and/or the putative transcobalamin-transcobalamin receptor interaction domain.

Published
2010

11. Predictive factors of cochlear implant outcomes in the elderly

Author

Olivier Sterkers, Mathieu Marx, Bernard Fraysse, Françoise Sterkers-Artieres, Bernard Meyer, Geneviève Lina-Granade, Bruno Frachet, Michel Mondain, Christine Poncet, Didier Bouccara, Jean-Pierre Bebear, Philippe Bordure, Benoit Godey, Alain Robier, Eric Truy, Isabelle Mosnier, Service d'oto-rhino-laryngologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon, Institut Claude Bernard - Physiologie et Pathologie ((IFR_2)), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Centre de recherche cerveau et cognition (CERCO), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'oto-rhino-laryngologie et d'oto-neurologie, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Neurosciences Sensorielles Comportement Cognition, Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Département d'ORL, chirurgie cervico-maxillo-faciale et d'audiophonologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, Centre hospitalier universitaire de Nantes (CHU Nantes), Service ORL et chirurgie cervico-faciale [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service d'ORL et de chirurgie maxillo-faciale [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Tenon [APHP], Service ORL [Avicenne], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris 13 (UP13)-Hôpital Avicenne, Institut Sophia Agrobiotech [Sophia Antipolis] (ISA), Institut National de la Recherche Agronomique (INRA)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Service ORL, CHU Pitié-Salpêtrière [APHP], Réhabilitation Chirurgicale mini-Invasive et Robotisée de l'Audition, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Auditory Implants and Skull Base Surgery, Hospital Pitié Salpêtrière (AP-HP, Otolaryngology Department, Unit of Otology), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des sciences du cerveau de Toulouse. (ISCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Service d'ORL et de chirurgie maxillo-faciale [Rennes] = ENT Head and Neck Surgery [Rennes], CHU Pontchaillou [Rennes], CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Institut Sophia Agrobiotech (ISA), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Recherche Agronomique (INRA), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Advanced Bionics AG (Stafa, Switzerland), Cochlear France (Saint-Aubin, France), Vibrant Medel Hearing technology (Sofia Antipolis, France), Oticon medical/Neurelec (Vallauris, France), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Service ORL, otoneurologie et ORL pédiatrique [CHU Toulouse], Pôle Céphalique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Avicenne

Subjects
Hearing aid, Male, Longitudinal study, medicine.medical_specialty, Speech perception, Physiology, Hearing loss, medicine.medical_treatment, Population, Audiology, 03 medical and health sciences, Speech and Hearing, 0302 clinical medicine, Hearing Aids, Quality of life, Risk Factors, Cochlear implant, medicine, otorhinolaryngologic diseases, Humans, 030223 otorhinolaryngology, education, Hearing Loss, Aged, Aged, 80 and over, education.field_of_study, business.industry, Age Factors, Cochlear Implantation, Sensory Systems, Treatment Outcome, Otorhinolaryngology, Cardiovascular Diseases, Speech Perception, Female, [SDV.IB]Life Sciences [q-bio]/Bioengineering, sense organs, medicine.symptom, business, 030217 neurology & neurosurgery, Tinnitus
Abstract

Objective: To analyze predictive factors of cochlear implant outcomes and postoperative complications in the elderly. Study Design: Prospective, longitudinal study performed in 10 tertiary referral centers. Methods: Ninety-four patients aged 65-85 years with a profound, postlingual hearing loss were evaluated before implantation, at time of activation, and 6 and 12 months after cochlear implantation. Speech perception and lipreading were measured using disyllabic word recognition in quiet and noise, and lipreading using disyllabic words and sentences. The influence of preoperative factors on speech perception in quiet and noise at 12 months was tested in a multivariate analysis. Complications, presence of tinnitus and of vestibular symptoms were collected at each evaluation. Results: The effect of age was observed only in difficult noisy conditions at SNR 0 dB. Lipreading ability for words and sentences was negatively correlated with speech perception in quiet and noise. Better speech perception scores were observed in patients with shorter duration of hearing deprivation, persistence of residual hearing for the low frequencies, the use of a hearing aid before implantation, the absence of cardiovascular risk factors, and in those with implantation in the right ear. General and surgical complications were very rare, and the percentage of vestibular symptoms remained stable over time. Conclusion:This study demonstrates that cochlear implantation in the elderly is a well-tolerated procedure and an effective method to improve communication ability. Advanced age has a low effect on cochlear implant outcome. Analyses of predictive factors in this population provide a convincing argument to recommend treatment with cochlear implantation as early as possible in elderly patients with confirmed diagnosis of a severe-to-profound hearing loss and with only limited benefit from hearing aid use in one ear.

Published
2014

12. Relative Frequencies of Inherited Retinal Dystrophies and Optic Neuropathies in Southern France: Assessment of 21-year Data Management

Author

Véronique Paquis-Flucklinger, Corinne Baudoin, Maxime Hebrard, José-Alain Sahel, Christina Zeitz, Bernd Wissinger, Jean-Michel Rozet, Anne-Françoise Roux, Isabelle Audo, Isabelle Perrault, Pascal Reynier, Hélène Dollfus, Claire-Marie Dhaenens, Mireille Claustres, Cécile Delettre, Christian P. Hamel, Dominique Bonneau, Catherine Blanchet, Benoit Arveiler, Béatrice Bocquet, Patrizia Amati-Bonneau, Audrey Sénéchal, Jean-Paul Bonnefont, Marie-Odile Surget, Isabelle Meunier, Suzanne Kohl, Gaël Manes, Virginie Marquette, Josseline Kaplan, Annie Lacroux, Patrick Calvas, Neuroimmunologie des annélides (NA), Université de Lille, Sciences et Technologies-Centre National de la Recherche Scientifique (CNRS), Épidémiologie et prévention : environnement et efficacité des interventions (EPIPREV), Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Méthodes et Algorithmes pour la Bioinformatique (MAB), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier (LIRMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Mitochondrie : Régulations et Pathologie, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), CHU Toulouse [Toulouse], Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Molecular Genetics Laboratory [Tuebingen, Germany] (Centre for Ophthalmology), Institute for Ophthalmic Research [Tuebingen, Germany]-University Clinics Tuebingen [Germany], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Institut des Neurosciences de Montpellier (INM), 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, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), 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, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Université Nice Sophia Antipolis (... - 2019) (UNS), University Clinics Tuebingen [Germany]-Institute for Ophthalmic Research [Tuebingen, Germany], and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Pathology, genetic structures, Epidemiology, Usher syndrome, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Peripherins, MESH: Intermediate Filament Proteins/genetics, MESH: Eye Proteins/genetics, MESH: Molecular Diagnostic Techniques, MESH: Membrane Glycoproteins/genetics, MESH: Optic Nerve Diseases/diagnosis, Polymerase Chain Reaction, Optic neuropathy, 0302 clinical medicine, MESH: Aged, 80 and over, Intermediate Filament Proteins, MESH: Child, Optic Nerve Diseases, Outpatient clinic, MESH: DNA Mutational Analysis, Child, Aged, 80 and over, MESH: Aged, 0303 health sciences, Extracellular Matrix Proteins, MESH: Retinal Dystrophies/genetics, Membrane Glycoproteins, macular dystrophy, MESH: Middle Aged, MESH: France/epidemiology, Inherited retinal dystrophies, Eye Diseases, Hereditary, Macular dystrophy, Middle Aged, inherited optic neuropathies, MESH: Infant, 3. Good health, MESH: Optic Nerve Diseases/genetics, Molecular Diagnostic Techniques, MESH: Young Adult, Child, Preschool, Myosin VIIa, MESH: ATP-Binding Cassette Transporters/genetics, Female, France, MESH: Peripherins, MESH: Retinal Dystrophies/epidemiology, Retinal Dystrophies, Retinopathy, Adult, medicine.medical_specialty, MESH: Mutation, Adolescent, Nerve Tissue Proteins, Myosins, 03 medical and health sciences, Young Adult, Retinitis pigmentosa, molecular diagnosis, medicine, Humans, MESH: Myosin VIIa, pigmentary retinopathy, Eye Proteins, 030304 developmental biology, Aged, MESH: Adolescent, MESH: Extracellular Matrix Proteins/genetics, MESH: Humans, business.industry, MESH: Child, Preschool, Infant, MESH: Adult, MESH: Eye Diseases, Hereditary/epidemiology, MESH: Polymerase Chain Reaction, medicine.disease, Dermatology, MESH: Myosins/genetics, MESH: Nerve Tissue Proteins/genetics, eye diseases, MESH: Male, Stargardt disease, Ophthalmology, Mutation, 030221 ophthalmology & optometry, MESH: Eye Diseases, Hereditary/genetics, ATP-Binding Cassette Transporters, sense organs, MESH: Optic Nerve Diseases/epidemiology, business, MESH: Retinal Dystrophies/diagnosis, MESH: Female, MESH: Eye Diseases, Hereditary/diagnosis
Abstract

International audience; PURPOSE:Inherited retinal dystrophies (IRDs) and inherited optic neuropathies (IONs) are rare diseases defined by specific clinical and molecular features. The relative prevalence of these conditions was determined in Southern France.METHODS:Patients recruited from a specialized outpatient clinic over a 21-year period underwent extensive clinical investigations and 107 genes were screened by polymerase chain reaction/sequencing.RESULTS:There were 1957 IRD cases (1481 families) distributed in 70% of pigmentary retinopathy cases (56% non-syndromic, 14% syndromic), 20% maculopathies and 7% stationary conditions. Patients with retinitis pigmentosa were the most frequent (47%) followed by Usher syndrome (10.8%). Among non-syndromic pigmentary retinopathy patients, 84% had rod-cone dystrophy, 8% cone-rod dystrophy and 5% Leber congenital amaurosis. Macular dystrophies were encountered in 398 cases (30% had Stargardt disease and 11% had Best disease). There were 184 ION cases (127 families) distributed in 51% with dominant optic neuropathies, 33% with recessive/sporadic forms and 16% with Leber hereditary optic neuropathy. Positive molecular results were obtained in 417/609 families with IRDs (68.5%) and in 27/58 with IONs (46.5%). The sequencing of 5 genes (ABCA4, USH2A, MYO7A, RPGR and PRPH2) provided a positive molecular result in 48% of 417 families with IRDs. Except for autosomal retinitis pigmentosa, in which less than half the families had positive molecular results, about 75% of families with other forms of retinal conditions had a positive molecular diagnosis.CONCLUSIONS:Although gene discovery considerably improved molecular diagnosis in many subgroups of IRDs and IONs, retinitis pigmentosa, accounting for almost half of IRDs, remains only partly molecularly defined.

Published
2013

13. Non-USH2A mutations in USH2 patients

Author

Lise Larrieu, David Baux, Catherine Blanchet, Hélène Dollfus, Caroline Abadie, Bertrand Isidor, James Lespinasse, Anne-Françoise Roux, Christel Vaché, Patrick Calvas, Sylvie Odent, Christian P. Hamel, Thomas Besnard, Sue Malcolm, Geneviève Lina-Granade, Mireille Claustres, Gilles Morin, Albert David, Patricia Blanchet, Sylvie Tuffery-Giraud, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, Service de génétique clinique [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Unité de Génétique Médicale et Foetopathologie, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Service de génétique médicale, CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Service de Génétique Médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Département d'ORL, chirurgie cervico-maxillo-faciale et d'audiophonologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Département de Génétique Chromosomique, Bâtiment Hôtel Dieu - Centre Hospitalier de Chambéry, Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Amiens-Picardie, Clinical and Molecular Genetics, University College of London [London] (UCL)-Institute of Child Health, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), De Villemeur, Hervé, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)

Subjects
DFNB31, GPR98, Usher syndrome, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, medicine.disease_cause, Polymerase Chain Reaction, Receptors, G-Protein-Coupled, functional analysis, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Missense mutation, Humans, molecular analysis, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Gene, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Mutation, Extracellular Matrix Proteins, [SDV.GEN]Life Sciences [q-bio]/Genetics, Haplotype, Membrane Proteins, medicine.disease, Membrane protein, Haplotypes, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, RNA splicing, Usher Syndromes, 030217 neurology & neurosurgery, Minigene
Abstract

International audience; We have systematically analyzed the two known minor genes involved in Usher syndrome type 2, DFNB31 and GPR98, for mutations in a cohort of 31 patients not linked to USH2A. PDZD7, an Usher syndrome type 2 (USH2) related gene, was analyzed when indicated. We found that mutations in GPR98 contribute significantly to USH2. We report 17 mutations in 10 individuals, doubling the number of GPR98 mutations reported to date. In contrast to mutations in usherin, the mutational spectrum of GPR98 predominantly results in a truncated protein product. This is true even when the mutation affects splicing, and we have incorporated a splicing reporter minigene assay to show this, where appropriate. Only two mutations were found which we believe to be genuine missense changes. Discrepancy in the mutational spectrum between GPR98 and USH2A is discussed. Only two patients were found with mutations in DFNB31, showing that mutations of this gene contribute to only a very small extent to USH2. Close examination of the clinical details, where available, for patients in whom no mutation was found in USH2A, GPR98, or DFNB31, showed that most of them had atypical features. In effect, these three genes account for the vast majority of USH2 patients and their analysis provide a robust pathway for routine molecular diagnosis.

Published
2012

14. Usher syndrome type 2 caused by activation of an USH2A pseudoexon: Implications for diagnosis and therapy

Author

Gema García-García, Lise Larrieu, Thomas Besnard, José Luis Millán, Sue Malcolm, Mireille Claustres, Hanno J. Bolz, Christel Vaché, David Baux, Catherine Blanchet, Anne-Françoise Roux, Christian P. Hamel, Pauline le Berre, Caroline Abadie, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique clinique [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, Centre Nacional de Microelectrònica (CNM), Universitat Autònoma de Barcelona (UAB), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Clinical and Molecular Genetics, University College of London [London] (UCL)-Institute of Child Health, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], and Institut des Neurosciences de Montpellier (INM)

Subjects
Male, Genotype, Sequence analysis, Usher syndrome, Hearing Loss, Sensorineural, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Molecular Sequence Data, Genes, Recessive, Biology, Bioinformatics, Severity of Illness Index, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, Exome, Gene, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Extracellular Matrix Proteins, Base Sequence, Sequence Analysis, RNA, Haplotype, Exons, Oligonucleotides, Antisense, medicine.disease, 3. Good health, Pedigree, Europe, Haplotypes, Case-Control Studies, Mutation (genetic algorithm), Mutation, Female, Usher Syndromes, 030217 neurology & neurosurgery, Retinitis Pigmentosa, Minigene
Abstract

International audience; USH2A sequencing in three affected members of a large family, referred for the recessive USH2 syndrome, identified a single pathogenic alteration in one of them and a different mutation in the two affected nieces. As the patients carried a common USH2A haplotype, they likely shared a mutation not found by standard sequencing techniques. Analysis of RNA from nasal cells in one affected individual identified an additional pseudoexon (PE) resulting from a deep intronic mutation. This was confirmed by minigene assay. This is the first example in Usher syndrome (USH) with a mutation causing activation of a PE. The finding of this alteration in eight other individuals of mixed European origin emphasizes the importance of including RNA analysis in a comprehensive diagnostic service. Finally, this mutation, which would not have been found by whole-exome sequencing, could offer, for the first time in USH, the possibility of therapeutic correction by antisense oligonucleotides (AONs).

Published
2012

15. Dominant optic atrophy

Author

Pascal Reynier, Patrizia Amati-Bonneau, Cécile Delettre, Dominique Bonneau, Dan Milea, Christian P. Hamel, Vincent Procaccio, Guy Lenaers, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Glostrup University Hospital, This work was supported by the INSERM, the CNRS, Université Montpellier I et II, France and the University of Angers, France, and by an European E-Rareprogram., BMC, Ed., and Institut des Neurosciences de Montpellier (INM)

Subjects
medicine.medical_specialty, Pathology, Visual acuity, genetic structures, Denmark, lcsh:Medicine, [SDV.GEN] Life Sciences [q-bio]/Genetics, Review, Retinal ganglion, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Internal medicine, Optic Atrophy, Autosomal Dominant, medicine, Prevalence, Humans, Genetics(clinical), Pharmacology (medical), Genetics (clinical), 030304 developmental biology, Medicine(all), 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Optic disc pallor, business.industry, lcsh:R, General Medicine, medicine.disease, Founder Effect, eye diseases, 3. Good health, Visual field, Peripheral neuropathy, Endocrinology, Optic nerve, sense organs, medicine.symptom, business, Chronic progressive external ophthalmoplegia, 030217 neurology & neurosurgery
Abstract

Definition of the disease Dominant Optic Atrophy (DOA) is a neuro-ophthalmic condition characterized by a bilateral degeneration of the optic nerves, causing insidious visual loss, typically starting during the first decade of life. The disease affects primary the retinal ganglion cells (RGC) and their axons forming the optic nerve, which transfer the visual information from the photoreceptors to the lateral geniculus in the brain. Epidemiology The prevalence of the disease varies from 1/10000 in Denmark due to a founder effect, to 1/30000 in the rest of the world. Clinical description DOA patients usually suffer of moderate visual loss, associated with central or paracentral visual field deficits and color vision defects. The severity of the disease is highly variable, the visual acuity ranging from normal to legal blindness. The ophthalmic examination discloses on fundoscopy isolated optic disc pallor or atrophy, related to the RGC death. About 20% of DOA patients harbour extraocular multi-systemic features, including neurosensory hearing loss, or less commonly chronic progressive external ophthalmoplegia, myopathy, peripheral neuropathy, multiple sclerosis-like illness, spastic paraplegia or cataracts. Aetiology Two genes (OPA1, OPA3) encoding inner mitochondrial membrane proteins and three loci (OPA4, OPA5, OPA8) are currently known for DOA. Additional loci and genes (OPA2, OPA6 and OPA7) are responsible for X-linked or recessive optic atrophy. All OPA genes yet identified encode mitochondrial proteins embedded in the inner membrane and ubiquitously expressed, as are the proteins mutated in the Leber Hereditary Optic Neuropathy. OPA1 mutations affect mitochondrial fusion, energy metabolism, control of apoptosis, calcium clearance and maintenance of mitochondrial genome integrity. OPA3 mutations only affect the energy metabolism and the control of apoptosis. Diagnosis Patients are usually diagnosed during their early childhood, because of bilateral, mild, otherwise unexplained visual loss related to optic discs pallor or atrophy, and typically occurring in the context of a family history of DOA. Optical Coherence Tomography further discloses non-specific thinning of retinal nerve fiber layer, but a normal morphology of the photoreceptors layers. Abnormal visual evoked potentials and pattern ERG may also reflect the dysfunction of the RGCs and their axons. Molecular diagnosis is provided by the identification of a mutation in the OPA1 gene (75% of DOA patients) or in the OPA3 gene (1% of patients). Prognosis Visual loss in DOA may progress during puberty until adulthood, with very slow subsequent chronic progression in most of the cases. On the opposite, in DOA patients with associated extra-ocular features, the visual loss may be more severe over time. Management To date, there is no preventative or curative treatment in DOA; severely visually impaired patients may benefit from low vision aids. Genetic counseling is commonly offered and patients are advised to avoid alcohol and tobacco consumption, as well as the use of medications that may interfere with mitochondrial metabolism. Gene and pharmacological therapies for DOA are currently under investigation.

Published
2012

16. RP1 and autosomal dominant rod-cone dystrophy: novel mutations, a review of published variants, and genotype-phenotype correlation.: RP1mutations in French adRP patients

Author

Audo, Isabelle, Mohand-Saïd, Saddek, Dhaenens, Claire-Marie, Germain, Aurore, Orhan, Elise, Antonio, Aline, Hamel, Christian, Sahel, José-Alain, Bhattacharya, Shomi, Zeitz, Christina, Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UCL-Institute of Ophthalmology, UF Génopathies - Laboratoire de Biochimie et Biologie Moléculaire [Lille] (LBBM), Université de Lille, Sciences et Technologies-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation Ophtalmologique Adolphe de Rothschild, Department of Celular Therapy and Regenerative Medicine (CABIMER), Andalusian Molecular Biology and Regenerative Medicine Centre, The project was financially supported by the Department of Paris, Foundation Fighting Blindness (I.A. FFB Grant N°: CD-CL-0808-0466-CHNO and the CIC503 recognized as an FFB center, FFB Grant No: C-CMM-0907-0428-INSERM04), ANR (S.S.B). NIHR Biomedical Research Centre for Ophthalmology and The Special Trustees of Moorfields Eye Hospital London, Foundation Voir et Entendre (C.Z) and French Ministry of Health (C.H. PHRC # 2008-A01238-47)., and Marazova, Katia

Subjects
[SDV.GEN]Life Sciences [q-bio]/Genetics, sense organs, [SDV.GEN] Life Sciences [q-bio]/Genetics, eye diseases
Abstract

International audience; Rod-cone dystrophies (RP) are a clinically and genetically heterogeneous group of inherited retinal disorders characterized by photoreceptor degeneration. RP1 is a major gene underlying autosomal dominant (ad) RP though prevalence figures vary depending on the origin of the cases from 0%-10% of all adRP. Some mutations in RP1 also lead to autosomal recessive RP. Herein we review all previously reported and several novel RP1 mutations in relation to the associated phenotype in patients from a French adRP cohort. Prevalence studies from this cohort show that 5.3% of the cases have RP1 mutations. This is in accordance with other studies reported from UK and USA. The majority of mutations represent truncating mutations which are located in a hot spot region of the gene. Similarly, we identified in total four novel deletions and nonsense mutations, of which two may represent recurrent mutations in this population. In addition a novel missense mutation of uncertain pathogenicity was identified. Including our findings, to date 43 RP1 mutations are known to cause adRP. Variable penetrance of the disease was observed in our and other cohorts. Most patients with RP1 mutations show classical signs of RP with relatively preserved central vision and visual field. ©2011 Wiley Periodicals, Inc.

Published
2012

17. Combining gene mapping and phenotype assessment for fast mutation finding in non-consanguineous autosomal recessive retinitis pigmentosa families

Author

Gaël Manes, Isabelle Meunier, Maxime Hebrard, Diana Zelenika, Audrey Sénéchal, Béatrice Bocquet, Delphine Coustes-Chazalette, Anne Bolland-Augé, Christian P. Hamel, Emilie Hérald, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut des Neurosciences de Montpellier (INM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)

Subjects
Adult, Male, Candidate gene, Adolescent, Fundus Oculi, Genome-wide association study, Biology, Compound heterozygosity, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Gene mapping, Genotype, Retinitis pigmentosa, Genetics, medicine, Humans, Child, Gene, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Base Sequence, Chromosome Mapping, autosomal recessive inheritance, gene mapping, Sequence Analysis, DNA, Middle Aged, medicine.disease, Phenotype, Pedigree, non consanguineous families, phenotype characterization, Child, Preschool, Mutation, 030221 ophthalmology & optometry, Female, Retinitis Pigmentosa, Genome-Wide Association Study
Abstract

Among inherited retinal dystrophies, autosomal recessive retinitis pigmentosa (arRP) is the most genetically heterogenous condition with 32 genes currently known that account for ∼60 % of patients. Molecular diagnosis thus requires the tedious systematic sequencing of 506 exons. To rapidly identify the causative mutations, we devised a strategy that combines gene mapping and phenotype assessment in small non-consanguineous families. Two unrelated sibships with arRP had whole-genome scan using SNP microchips. Chromosomal regions were selected by calculating a score based on SNP coverage and genotype identity of affected patients. Candidate genes from the regions with the highest scores were then selected based on phenotype concordance of affected patients with previously described phenotype for each candidate gene. For families RP127 and RP1459, 33 and 40 chromosomal regions showed possible linkage, respectively. By comparing the scores with the phenotypes, we ended with one best candidate gene for each family, namely tubby-like protein 1 (TULP1) and C2ORF71 for RP127 and RP1459, respectively. We found that RP127 patients were compound heterozygous for two novel TULP1 mutations, p.Arg311Gln and p.Arg342Gln, and that RP1459 patients were compound heterozygous for two novel C2ORF71 mutations, p.Leu777PhefsX34 and p.Leu777AsnfsX28. Phenotype assessment showed that TULP1 patients had severe early onset arRP and that C2ORF71 patients had a cone rod dystrophy type of arRP. Only two affected individuals in each sibship were sufficient to lead to mutation identification by screening the best candidate gene selected by a combination of gene mapping and phenotype characterization.

Published
2011

18. Combining gene mapping and phenotype assessment for fast mutation finding in non consanguineous autosomal recessive retinitis pigmentosa

Author

Hébrard, Maxime, Bocquet, Béatrice, Meunier, Isabelle, Coustes-Chazalette, Delphine, Hérald, Emilie, Sénéchal, Audrey, Bolland Augé, Anne, Zelenika, Diana, Manès, Gaël, Hamel, Christian P, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, Centre National de Génotypage (CNG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
non consanguineous families, retinitis pigmentosa, phenotype characterization, autosomal recessive inheritance, gene mapping
Abstract

International audience; Among inherited retinal dystrophies, autosomal recessive retinitis pigmentosa (arRP) is the most genetically heterogenous condition with 32 genes currently known that account for ~60 % of patients. Molecular diagnosis thus requires the tedious systematic sequencing of 506 exons. To rapidly identify the causative mutations, we devised a strategy that combines gene mapping and phenotype assessment in small non consanguineous families. Two unrelated sibships with arRP had whole-genome scan using SNP microchips. Chromosomal regions were selected by calculating a score based on SNP coverage and genotype identity of affected patients. Candidate genes from the regions with the highest scores were then selected based on phenotype concordance of affected patients with previously described phenotype for each candidate gene. For families RP127 and RP1459, 33 and 40 chromosomal regions showed possible linkage, respectively. By comparing the scores with the phenotypes, we ended with one best candidate gene for each family, namely TULP1 and C2ORF71 for RP127 and RP1459, respectively. We found that RP127 patients were compound heterozygous for 2 novel TULP1 mutations, p.Arg311Gln and p.Arg342Gln, and that RP1459 patients were compound heterozygous for 2 novel C2ORF71 mutations, p.Leu777PhefsX34 and p.Leu777AsnfsX28. Phenotype assessment showed that TULP1 patients had severe early onset arRP and that C2ORF71 patients had a cone rod dystrophy type of arRP. Only 2 affected individuals in each sibship were sufficient to lead to mutation identification by screening the best candidate gene selected by a combination of gene mapping and phenotype characterization.

Published
2011

19. A novel locus (CORD12) for autosomal dominant cone-rod dystrophy on chromosome 2q24.2-2q33.1

Author

Gaël Manes, Anne Bolland-Augé, Béatrice Bocquet, Maxime Hebrard, Isabelle Meunier, Delphine Coustes-Chazalette, Christian P. Hamel, Diana Zelenika, Audrey Sénéchal, Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), The work was supported by private foundations (Information Recherche sur la Rétinite Pigmentaire, Retina France, SOS Rétinite and UNADEV), Centre National de Génotypage and INSERM. Special thanks to UNADEV which supports fellowship for GM and MH., Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, and BMC, Ed.

Subjects
Male, lcsh:Internal medicine, medicine.medical_specialty, lcsh:QH426-470, genetic structures, Genetic Linkage, Locus (genetics), [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Genetic linkage, Retinitis pigmentosa, medicine, Genetics, Humans, Genetics(clinical), lcsh:RC31-1245, Gene, Genetics (clinical), 030304 developmental biology, Genes, Dominant, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Cytogenetics, Dystrophy, Chromosome Mapping, Middle Aged, medicine.disease, Molecular biology, eye diseases, Human genetics, Pedigree, lcsh:Genetics, Chromosomes, Human, Pair 2, 030221 ophthalmology & optometry, Female, sense organs, Retinal Dystrophies, Retinitis Pigmentosa, Microsatellite Repeats, Research Article
Abstract

Background Rod-cone dystrophy, also known as retinitis pigmentosa (RP), and cone-rod dystrophy (CRD) are degenerative retinal dystrophies leading to blindness. To identify new genes responsible for these diseases, we have studied one large non consanguineous French family with autosomal dominant (ad) CRD. Methods Family members underwent detailed ophthalmological examination. Linkage analysis using microsatellite markers and a whole-genome SNP analysis with the use of Affymetrix 250 K SNP chips were performed. Five candidate genes within the candidate region were screened for mutations by direct sequencing. Results We first excluded the involvement of known adRP and adCRD genes in the family by genotyping and linkage analysis. Then, we undertook a whole-genome scan on 22 individuals in the family. The analysis revealed a 41.3-Mb locus on position 2q24.2-2q33.1. This locus was confirmed by linkage analysis with specific markers of this region. The maximum LOD score was 2.86 at θ = 0 for this locus. Five candidate genes, CERKL, BBS5, KLHL23, NEUROD1, and SF3B1 within this locus, were not mutated. Conclusion A novel locus for adCRD, named CORD12, has been mapped to chromosome 2q24.2-2q33.1 in a non consanguineous French family.

Published
2011

20. Genotype-phenotype correlations of TGFBI p.Leu509Pro, p.Leu509Arg, p.Val613Gly, and the allelic association of p.Met502Val-p.Arg555Gln mutations

Author

Niel-Butschi F, Kantelip B, Iwaszkiewicz J, Zoete V, Boimard M, Delpech M, Jl, Bourges, Renard G, D'Hermies F, Pj, Pisella, Hamel C, Delbosc B, Sophie Valleix, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Laboratoire d'anatomie pathologique [Besancon], Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz-Université de Franche-Comté ( UFC ), Hôtel-Dieu, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 ( UPD5 ), Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Gui De Chaulliac, Service d'ophtalmologie [Besançon], Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Laboratoire de Biochimie et Génétique Moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Service d'Anatomie pathologique [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, Service d'ophtalmologie [CHRU Besançon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Viala, Pascale, Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz-Université de Franche-Comté (UFC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) ( CEF2P / CARCINO ), and Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté [COMUE] ( UBFC ) -Université de Franche-Comté ( UFC )

Subjects
Male, Models, Molecular, MESH: Extracellular Matrix Proteins, MESH : Molecular Sequence Data, MESH : Algeria, Genetic Linkage, MESH : Genotype, MESH: Amino Acid Sequence, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Genotype, MESH: Aged, 80 and over, Gene Frequency, Transforming Growth Factor beta, MESH : Gene Frequency, MESH : Female, Bowman Membrane, MESH: Genetic Association Studies, Aged, 80 and over, Corneal Dystrophies, Hereditary, Extracellular Matrix Proteins, MESH: Middle Aged, MESH : Amino Acid Sequence, MESH : Infant, Middle Aged, MESH : Adult, MESH: Infant, Pedigree, MESH : Phenotype, Phenotype, Female, France, MESH : Mutation, MESH: Algeria, MESH: Models, Molecular, Research Article, Adult, MESH: Mutation, Genotype, MESH: Pedigree, MESH : Models, Molecular, MESH : Bowman Membrane, MESH : Male, Molecular Sequence Data, MESH: Genetic Linkage, MESH: Corneal Dystrophies, Hereditary, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Phenotype, MESH : Extracellular Matrix Proteins, [SDV.CAN] Life Sciences [q-bio]/Cancer, Algeria/ethnology, Alleles, Amino Acid Sequence, Bowman Membrane/metabolism, Bowman Membrane/pathology, Corneal Dystrophies, Hereditary/classification, Corneal Dystrophies, Hereditary/epidemiology, Corneal Dystrophies, Hereditary/ethnology, Corneal Dystrophies, Hereditary/genetics, Corneal Dystrophies, Hereditary/pathology, Extracellular Matrix Proteins/genetics, Extracellular Matrix Proteins/metabolism, France/epidemiology, Genetic Association Studies, Humans, Infant, Mutation, Transforming Growth Factor beta/genetics, Transforming Growth Factor beta/metabolism, MESH: Gene Frequency, MESH : Middle Aged, MESH : Aged, 80 and over, MESH : France, MESH: Transforming Growth Factor beta, MESH: Humans, MESH: Molecular Sequence Data, MESH: Alleles, MESH : Humans, MESH: Adult, MESH : Genetic Association Studies, MESH : Genetic Linkage, MESH: Male, eye diseases, MESH: France, MESH : Transforming Growth Factor beta, Algeria, MESH : Pedigree, MESH : Corneal Dystrophies, Hereditary, MESH : Alleles, MESH: Female, MESH: Bowman Membrane
Abstract

International audience; PURPOSE: Investigate the genotype-phenotype correlations for five TGFBI (transforming growth factor, beta-induced) mutations including one novel pathogenic variant and one complex allele affecting the fourth FAS1 domain of keratoepithelin, and their potential effects on the protein's structure. METHODS: Three unrelated families were clinically diagnosed with lattice corneal dystrophy (CD) and one with an unclassified CD of Bowman's layer. Mutations in the TGFBI gene were detected by direct sequencing, and the functional impact of each variant was predicted using in silico algorithms. Corneal phenotypes, including histological examinations, were compared with the literature data. Furthermore, molecular modeling studies of these mutations were performed. RESULTS: Two distinct missense mutations affecting the same residue at position 509 of keratoepithelin: p.Leu509Pro (c.1526T>C) and p.Leu509Arg (c.1526T>G) were found to be associated with a lattice-type CD. The novel p.Val613Gly (c.1828T>G) TGFBI mutation was found in a sporadic case of an Algerian individual affected by lattice CD. Finally, the Bowman's layer CD was linked to the association in cis of the p.Met502Val and p.Arg555Gln variants, leading to the reclassification of this CD as atypical Thiel-Behnke CD. Structural modeling of these TGFBI mutations argues in favor of these mutations being responsible for instability and/or incorrect folding of keratoepithelin, predictions that are compatible with the clinical diagnoses. CONCLUSIONS: Description of a novel TGFBI mutation and a complex TGFBI allele further extends the mutational spectrum of TGFBI. Moreover, we show convincing evidence that TGFBI mutations affecting Leu509 are linked to the lattice phenotype in two unrelated French families, contrasting with findings previously reported. The p.Leu509Pro was reported to be associated with both amyloid and non-amyloid aggregates, whereas p.Leu509Arg has been described as being responsible for Epithelial Basement Membrane Dystrophy (EBMD).

Published
2011

21. Nasal epithelial cells are a reliable source to study splicing variants in Usher syndrome

Author

Mireille Claustres, Catherine Blanchet, Michel Mondain, Christel Vaché, Anne-Françoise Roux, Thomas Besnard, Lise Larrieu, Valérie Faugère, David Baux, Sue Malcolm, Christian P. Hamel, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, Clinical and Molecular Genetics, Institute of Child Health, and Université Montpellier 1 (UM1)

Subjects
Nonsynonymous substitution, MYO7A, Usher syndrome, RNA Splicing, Cadherin Related Proteins, Gene Expression, Cell Cycle Proteins, Nerve Tissue Proteins, Biology, Myosins, Sensitivity and Specificity, Receptors, G-Protein-Coupled, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, otorhinolaryngologic diseases, Humans, Protein Isoforms, Genetic Predisposition to Disease, RNA, Messenger, Gene, Genetics (clinical), 030304 developmental biology, Adaptor Proteins, Signal Transducing, 0303 health sciences, Messenger RNA, Extracellular Matrix Proteins, Base Sequence, Reverse Transcriptase Polymerase Chain Reaction, RNA, Life Sciences, Membrane Proteins, Reproducibility of Results, Epithelial Cells, medicine.disease, Cadherins, Cytoskeletal Proteins, Molecular Diagnostic Techniques, Myosin VIIa, RNA splicing, Mutation, RNA Splice Sites, Nasal Cavity, Usher Syndromes, 030217 neurology & neurosurgery, PCDH15
Abstract

We have shown that nasal ciliated epithelium, which can be easily biopsied under local anesthetic, provides a good source of RNA transcripts from eight of the nine known genes that cause Usher syndrome, namely, MYO7A, USH1C, CDH23, PCDH15, USH1G for Usher type 1, and USH2A, GPR98, WHRN for Usher type 2. Furthermore, the known or predicted effect on mRNA splicing of eight variants was faithfully reproduced in the biopsied sample as measured by nested RT-PCR. These included changes at the canonical acceptor site, changes within the noncanonical acceptor site and both synonymous and nonsynonymous amino acid changes. This shows that mRNA analysis by this method will help in assessing the pathogenic effect of variants, which is a major problem in the molecular diagnosis of Usher syndrome. Hum Mutat 31:1–8, 2010. © 2010 Wiley-Liss, Inc.

Published
2010

22. Spectrum of Rhodopsin Mutations in French Autosomal Dominant Rod–Cone Dystrophy Patients

Author

Gaël Manes, Shomi S. Bhattacharya, Veselina Moskova-Doumanova, Christian P. Hamel, José-Alain Sahel, Saddek Mohand-Said, Isabelle Audo, Xavier Zanlonghi, Marie-Elise Lancelot, Olivier Poch, Anne Friedrich, Aline Antonio, Christina Zeitz, Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Molecular Genetics, Institute of Ophthalmology, Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Exploration Fonctionnelle de la Vision, Clinique Sourdille, Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, The project was financially supported by Foundation Fighting Blindness (I.A.), Foundation Voir et Entendre and BQR, Université Pierre et Marie Curie6 (C.Z), PHRC national adRP (C H)., Marazova, Katia, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)

Subjects
Male, Retinal degeneration, genetic structures, DNA Mutational Analysis, Visual Acuity, [SDV.GEN] Life Sciences [q-bio]/Genetics, Gene mutation, medicine.disease_cause, Polymerase Chain Reaction, 0302 clinical medicine, Prevalence, Fluorescein Angiography, Child, Genes, Dominant, Genetics, 0303 health sciences, Mutation, biology, Middle Aged, Pedigree, 3. Good health, Phenotype, Rhodopsin, Female, France, Retinitis Pigmentosa, Tomography, Optical Coherence, Photoreceptor Cells, Vertebrate, Adult, Adolescent, Genotype, White People, Article, Young Adult, 03 medical and health sciences, Retinitis pigmentosa, Electroretinography, medicine, Rod-cone dystrophy, Humans, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Genetic heterogeneity, Point mutation, medicine.disease, eye diseases, 030221 ophthalmology & optometry, biology.protein, sense organs
Abstract

Rod-cone dystrophies, also called retinitis pigmentosa (RP), are a clinically and genetically heterogeneous group of inherited retinal disorders primarily affecting rods with secondary cone degeneration 1. RP patients initially often complain of night blindness. This is attributed to the primarily affected rods and clinical sign of the impaired rod function. Later on, when the secondary cone dysfunctions manifests, progressive visual field constriction, abnormal color vision and loss of central vision can be observed – signs of decreasing cone function. As the disease progresses and retinal dysfunction decreases, visual impairment increases: in some cases the disease may eventually result in very severe visual impairment or even blindness. RP is the most common inherited form of severe retinal degeneration, with a frequency of about 1 in 4000 births and more than 1 million affected individuals over the world. The mode of inheritance can be X-linked (5–15%) autosomal dominant (30–40%) or autosomal recessive (50–60%) The remaining patients represent isolated cases of which the inheritance trait can not be established 1. To date, 20 autosomal dominant RP (adRP) genes have been reported (http://www.sph.uth.tmc.edu/Retnet/). One of the major genes underlying this disorder is rhodopsin (RHO) coding for the light absorbing molecule that initiates the signal transmission cascade in rod photoreceptors. According to the literature, RHO mutation prevalence ranges from 0 to 50% cases of adRP in cohorts from various geographical origins, with higher numbers reported in the United States 2–18. The genetic and phenotypic heterogeneity is not only found in RP in general but also specifically reflected in adRP with RHO mutations: Over 120 mutations have been identified in different sites of the gene including specific hot spots (http://www.sph.uth.tmc.edu/Retnet/, http://www.hgmd.cf.ac.uk/ac/all.php, http://www.retina-international.org/sci-news/rhomut.htm) 19. Certain mutations in RHO lead to diffuse rod-cone dysfunction whereas other cases are implicated in a more restricted disease that may predominate in the inferior part of the retina such as in sector RP 20. Phenotypic classifications have been proposed to reflect this variability. In particular, Cideciyan and co-workers have distinguished two classes of disease expression with allele-specificity 21: class A mutants show severely generalized abnormal rod function early in life with a constant rate of cone disease progression across the retina with time. Class B mutants show more restricted disease and absent or lateonset night blindness. Other classifications have been proposed based on the underlying pathogenic mechanism involved in adRP due to RHO mutations. Mendes and co-workers classified the different types of mutations in 6 groups. Class I refers exclusively to rhodopsin mutations that fold correctly but are not transported to the outer segment. Class II, refers to mutations that misfold, are retained in the endopasmic reticulum (ER) and cannot easily reconstitute with 11-cis-retinal. Class III refers to mutations that affect endocytosis. Class IV mutations do not affect folding per se but might affect rhodopsin stability and posttranslational modification. Similarly, Class V mutations have no obvious folding defect but show an increased activation rate for transducin. Mutants that appear to fold correctly but lead to the constitutive activation of opsin in the absence of the chromophore and in the dark constitute Class VI. Other mutations with unclear biochemical or cellular defect, or uninvestigated defect were not classified 19. Our comprehensive study presented herein aim to investigate in detail a French adRP cohort coming from 2 different clinical centers, namely Quinze-Vingts hospital in Paris and the Centre Hospitalier Regional in Montpellier located in the south of France. We will present the prevalence of rhodopsin mutations in this cohort and show precise phenotype-genotype correlations. Novel mutations will be analyzed on its predicted pathogenic mechanism as well as frequently mutated sites will be presented as putative candidates for therapeutic approaches.

Published
2010

24. Increased steroidogenesis promotes early-onset and severe vision loss in females with OPA1 dominant optic atrophy.

Author

Sarzi E, Seveno M, Angebault C, Milea D, Rönnbäck C, Quilès M, Adrian M, Grenier J, Caignard A, Lacroux A, Lavergne C, Reynier P, Larsen M, Hamel CP, Delettre C, Lenaers G, and Müller A

Subjects
Adolescent, Animals, Apoptosis genetics, Disease Models, Animal, Female, Humans, Male, Mice, Mice, Transgenic, Mitochondria genetics, Mitochondria pathology, Mutant Proteins genetics, Optic Nerve pathology, Pregnenolone genetics, Pregnenolone metabolism, Retina pathology, Retinal Degeneration pathology, Sex Characteristics, GTP Phosphohydrolases genetics, Optic Atrophy, Autosomal Dominant genetics, Retinal Degeneration genetics, Retinal Ganglion Cells pathology
Abstract

OPA1 mutations are responsible for autosomal dominant optic atrophy (ADOA), a progressive blinding disease characterized by retinal ganglion cell (RGC) degeneration and large phenotypic variations, the underlying mechanisms of which are poorly understood. OPA1 encodes a mitochondrial protein with essential biological functions, its main roles residing in the control of mitochondrial membrane dynamics as a pro-fusion protein and prevention of apoptosis. Considering recent findings showing the importance of the mitochondrial fusion process and the involvement of OPA1 in controlling steroidogenesis, we tested the hypothesis of deregulated steroid production in retina due to a disease-causing OPA1 mutation and its contribution to the visual phenotypic variations. Using the mouse model carrying the human recurrent OPA1 mutation, we disclosed that Opa1 haploinsufficiency leads to very high circulating levels of steroid precursor pregnenolone in females, causing an early-onset vision loss, abolished by ovariectomy. In addition, steroid production in retina is also increased which, in conjunction with high circulating levels, impairs estrogen receptor expression and mitochondrial respiratory complex IV activity, promoting RGC apoptosis in females. We further demonstrate the involvement of Muller glial cells as increased pregnenolone production in female cells is noxious and compromises their role in supporting RGC survival. In parallel, we analyzed ophthalmological data of a multicentre OPA1 patient cohort and found that women undergo more severe visual loss at adolescence and greater progressive thinning of the retinal nerve fibres than males. Thus, we disclosed a gender-dependent effect on ADOA severity, involving for the first time steroids and Müller glial cells, responsible for RGC degeneration., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Published
2016
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25. OPA1-related disorders: Diversity of clinical expression, modes of inheritance and pathophysiology.

Author

Chao de la Barca JM, Prunier-Mirebeau D, Amati-Bonneau P, Ferré M, Sarzi E, Bris C, Leruez S, Chevrollier A, Desquiret-Dumas V, Gueguen N, Verny C, Hamel C, Miléa D, Procaccio V, Bonneau D, Lenaers G, and Reynier P

Subjects
Animals, Humans, GTP Phosphohydrolases genetics, GTP Phosphohydrolases metabolism, Optic Atrophy, Autosomal Dominant genetics, Optic Atrophy, Autosomal Dominant physiopathology
Abstract

Mutations in the Optic Atrophy 1 gene (OPA1) were first identified in 2000 as the main cause of Dominant Optic Atrophy, a disease specifically affecting the retinal ganglion cells and the optic nerve. Since then, an increasing number of symptoms involving the central, peripheral and autonomous nervous systems, with considerable variations of age of onset and severity, have been reported in OPA1 patients. This variety of phenotypes is attributed to differences in the effects of OPA1 mutations, to the mode of inheritance, which may be mono- or bi-allelic, and eventually to somatic mitochondrial DNA mutations. The diversity of the pathophysiological mechanisms involved in OPA1-related disorders is linked to the crucial role played by OPA1 in the maintenance of mitochondrial structure, genome and function. The neurological expression of these disorders highlights the importance of mitochondrial dynamics in neuronal processes such as dendritogenesis, axonal transport, and neuronal survival. Thus, OPA1-related disorders may serve as a paradigm in the wider context of neurodegenerative syndromes, particularly for the development of novel therapeutic strategies against these diseases., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Published
2016
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