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1. Genetic heterogeneity of congenital hearing impairment in Algerians from the Ghardaïa province

Author

Fatima Ammar-Khodja, Christine Petit, Malika Dahmani, Fabienne Wong Jun Tai, Malek Louha, Jean-Pierre Hardelin, Farid Boudjenah, Zied Riahi, Crystel Bonnet, Sonia Talbi, Université des Sciences et de la Technologie Houari Boumediene [Alger] (USTHB), Génétique et Physiologie de l'Audition, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hôpital de Frantz fanon, Hôpital Sidi Belloua, Service de Biochimie et de Biologie Moléculaire [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), This work was supported by grants from the Algerian government, LabEx Lifesenses (ANR-10-LABX-65), the Fondation BNP Paribas, the Fondation Raymonde & Guy Strittmatter., The authors thank the directors of deafness schools and the families for their participation in this study., ANR-10-LABX-0065,LIFESENSES,DES SENS POUR TOUTE LA VIE(2010), Université des Sciences et de la Technologie Houari Boumediene = University of Sciences and Technology Houari Boumediene [Alger] (USTHB), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Collège de France - Chaire Génétique et physiologie cellulaire

Subjects
0301 basic medicine, Male, MESH: Extracellular Matrix Proteins, [SDV]Life Sciences [q-bio], MESH: Calcium-Binding Proteins, MESH: Genetic Markers, Connexins, MESH: Membrane Transport Proteins, Consanguinity, Genetic heterogeneity, Medicine, TECTA, Exome sequencing, Genetics, education.field_of_study, Extracellular Matrix Proteins, biology, MESH: Genetic Heterogeneity, General Medicine, 3. Good health, Connexin 26, Sulfate Transporters, Myosin VIIa, Female, MESH: Algeria, GJB6, Genetic Markers, MESH: Mutation, Genetic counseling, Population, Myosins, GPI-Linked Proteins, Hearing impairment, 03 medical and health sciences, Monoallelic Mutation, otorhinolaryngologic diseases, Humans, MESH: Myosin VIIa, education, Hearing Loss, MESH: Hearing Loss, MESH: Consanguinity, MESH: Humans, business.industry, Calcium-Binding Proteins, Membrane Transport Proteins, MESH: Myosins, MESH: Sulfate Transporters, MESH: Male, MESH: Connexins, 030104 developmental biology, Otorhinolaryngology, Algeria, Pediatrics, Perinatology and Child Health, Mutation, biology.protein, MESH: GPI-Linked Proteins, business, MESH: Female
Abstract

International audience; Background: Consanguinity rate is high in Algeria, and the population is thus at high risk for genetic diseases transmitted on an autosomal recessive mode. Inherited congenital hearing impairment (HI) is a highly heterogeneous disorder, which affects approximately 1 in 800 Algerian newborns. Several hundreds of genes responsible for deafness have been reported among which more than one hundred are responsible for isolated deafness, of which 19 have already been reported to be involved in the Algerian population. This study focuses on patients from the Ghardaïa province, an ethnically and geographically isolated region of Southern Algeria that has the highest consanguinity rate in the country (56%).Methods: Eleven families, with at least two related members experiencing moderate to profound congenital HI, were recruited and screened for mutations in known HI genes.Results: A preliminary screening for common mutations in GJB2 and GJB6 identified the prevalent GJB2:c.35delG mutation in four families. Targeted exome sequencing further identified the causal mutations in the remaining seven families: CIB2:c.97C > T; p.(Arg33*), MYO7A:c.470+1G > A; p.(?), and SLC26A4:c.410C > T; p.(Ser137Leu) biallelic mutations in two families each, and a TECTA:c.2743 A > G; p.(Ile915Val) monoallelic mutation in the only family with autosomal dominant transmission of the HI. Of note, the missense mutations of SLC26A4 and TECTA had not been previously reported.Conclusion: These results further substantiate the genetic heterogeneity of HI, even in reportedly isolated populations. However, several families may harbor the same mutations as a result of a long history of marriages between relatives. This study has important implications for the HI molecular diagnosis strategy, and to develop genetic counseling for families originating from the Ghardaïa province of Algeria.

Published
2018
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2. CLINICAL PRESENTATION AND DISEASE COURSE OF USHER SYNDROME BECAUSE OF MUTATIONS IN MYO7A OR USH2A

Author

Testa, Francesco, Melillo, Paolo, Bonnet, Crystel, Marcelli, Vincenzo, de Benedictis, Antonella, Colucci, Raffaella, Gallo, Beatrice, Kurtenbach, Anne, Rossi, Settimio, Marciano, Elio, AURICCHIO, ALBERTO, Petit, Christine, Zrenner, Eberhart, Simonelli, Francesca, MARCIANO, ELIO, Second University of Naples-Caserta, University of Naples Federico II, 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), University of Tuebingen, Telethon Institute of Genetics and Medicine = Istituto Telethon di Genetica e Medicina (TIGEM), Institut Pasteur [Paris], Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), University of Naples Federico II = Università degli studi di Napoli Federico II, Institut Pasteur [Paris] (IP), Collège de France - Chaire Génétique et physiologie cellulaire, Testa, Francesco, Melillo, Paolo, Bonnet, Crystel, Marcelli, Vincenzo, de Benedictis, Antonella, Colucci, Raffaella, Gallo, Beatrice, Kurtenbach, Anne, Rossi, Settimio, Marciano, Elio, Auricchio, Alberto, Petit, Christine, Zrenner, Eberhart, and Simonelli, Francesca

Subjects
0301 basic medicine, Male, MESH: Extracellular Matrix Proteins, Pathology, Time Factors, genetic structures, visual acuity, Usher syndrome, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, medicine.disease_cause, MESH: Electroretinography, MESH: Visual Acuity, 0302 clinical medicine, Retrospective Studie, Medicine, Young adult, MESH: DNA Mutational Analysis, Mutation, Extracellular Matrix Proteins, MESH: Middle Aged, MESH: Retina, longitudinal study, MESH: DNA, General Medicine, MESH: Follow-Up Studies, Extracellular Matrix Protein, Middle Aged, Phenotype, Natural history, MYO7A, MESH: Tomography, Optical Coherence, MESH: Young Adult, Myosin VIIa, Disease Progression, Female, MESH: Disease Progression, Presentation (obstetrics), Usher Syndromes, Tomography, Optical Coherence, Human, Adult, visual field, medicine.medical_specialty, MESH: Mutation, Adolescent, Time Factor, Myosin, Myosins, MESH: Phenotype, Retina, Disease course, Follow-Up Studie, DNA Mutational Analysi, 03 medical and health sciences, Young Adult, USH2A, Internal medicine, otorhinolaryngologic diseases, Humans, MESH: Myosin VIIa, MESH: Usher Syndromes, Retrospective Studies, MESH: Adolescent, MESH: Humans, business.industry, MESH: Time Factors, MESH: Adult, MESH: Retrospective Studies, DNA, MESH: Myosins, medicine.disease, eye diseases, MESH: Male, Ophthalmology, 030104 developmental biology, 030221 ophthalmology & optometry, Visual Fields, electroretinography, MESH: Visual Fields, business, MESH: Female, Follow-Up Studies
Abstract

Purpose: To evaluate differences in the visual phenotype and natural history of Usher syndrome caused by mutations in MYO7A or USH2A, the most commonly affected genes of Usher syndrome Type I (USH1) and Type II (USH2), respectively.Methods: Eighty-eight patients with a clinical diagnosis of USH1 (26 patients) or USH2 (62 patients) were retrospectively evaluated. Of these, 48 patients had 2 disease-causing mutations in MYO7A (10 USH1 patients), USH2A (33 USH2 patients), and other USH (5 patients) genes. Clinical investigation included best-corrected visual acuity, Goldmann visual field, fundus photography, electroretinography, and audiologic and vestibular assessments. Longitudinal analysis was performed over a median follow-up time of 3.5 years.Results: Patients carrying mutations in MYO7A had a younger age of onset of hearing and visual impairments than those carrying mutations in USH2A, leading to an earlier diagnosis of the disease in the former patients. Longitudinal analysis showed that visual acuity and visual field decreased more rapidly in subjects carrying MYO7A mutations than in those carrying USH2A mutations (mean annual exponential rates of decline of 3.92 vs. 3.44% and of 8.52 vs. 4.97%, respectively), and the former patients reached legal blindness on average 15 years earlier than the latter.Conclusion: The current study confirmed a more severe progression of the retinal disease in USH1 patients rather than in USH2 patients. Furthermore, most visual symptoms (i.e., night blindness, visual acuity worsening) occurred at an earlier age in USH1 patients carrying mutations in MYO7A. Purpose: To evaluate differences in the visual phenotype and natural history of Usher syndrome caused by mutations in MYO7A or USH2A, the most commonly affected genes of Usher syndrome Type I (USH1) and Type II (USH2), respectively. Methods: Eighty-eight patients with a clinical diagnosis of USH1 (26 patients) or USH2 (62 patients) were retrospectively evaluated. Of these, 48 patients had 2 disease-causing mutations in MYO7A (10 USH1 patients), USH2A (33 USH2 patients), and other USH (5 patients) genes. Clinical investigation included best-corrected visual acuity, Goldmann visual field, fundus photography, electroretinography, and audiologic and vestibular assessments. Longitudinal analysis was performed over a median follow-up time of 3.5 years. Results: Patients carrying mutations in MYO7A had a younger age of onset of hearing and visual impairments than those carrying mutations in USH2A, leading to an earlier diagnosis of the disease in the former patients. Longitudinal analysis showed that visual acuity and visual field decreased more rapidly in subjects carrying MYO7A mutations than in those carrying USH2A mutations (mean annual exponential rates of decline of 3.92 vs. 3.44% and of 8.52 vs. 4.97%, respectively), and the former patients reached legal blindness on average 15 years earlier than the latter. Conclusion: The current study confirmed a more severe progression of the retinal disease in USH1 patients rather than in USH2 patients. Furthermore, most visual symptoms (i.e., night blindness, visual acuity worsening) occurred at an earlier age in USH1 patients carrying mutations in MYO7A.

Published
2017
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3. Cadherin-23, myosin VIIa and harmonin, encoded by Usher syndrome type I genes, form a ternary complex and interact with membrane phospholipids

Author

Sylviane Hoos, Jean-Pierre Hardelin, Christine Petit, Vincent Michel, Patrick England, Anne Houdusse, Amel Bahloul, Sylvie Nouaille, Génétique et Physiologie de l'Audition, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biophysique des Macromolécules et de leurs Interactions, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris], Institut Pasteur [Paris] (IP), Collège de France (CdF (institution)), This work was supported by LHW-Stiftung, Fondation Orange, Conny Maeva Foundation, ANR-05-MRAR-015-01, Raymonde and Guy Strittmatter Foundation (under the aegis of Fondation de France), FAUN Stiftung (Suchert Foundation). Funding to pay the Open Access Charge was provided by Unite de Genetique et Physiologie de l'Audition, Institut Pasteur, France., The authors thank Muriel Delepierre for NMR spectra, Raphaël Etournay and Alexandre Chenal for their advice in the preparation of LUV, Beatrice Amigues for myosin VIIa tail preparation, Bruno Baron for circular dichroism experiments, Jacqueline Levilliers for her help in the manuscript preparation and the staff of Dynamic Imaging platform of the Pasteur Institute., ANR-05-MRAR-0015,Usher type I,Physiopathologie du syndrome de Usher de type I : de la structure de la myosine VIIa et de l'harmonine à leur fonction dans les cellules ciliées auditives(2005), ENGLAND, Patrick, and Programme pluriannuel de recherche sur les maladies rares - Physiopathologie du syndrome de Usher de type I : de la structure de la myosine VIIa et de l'harmonine à leur fonction dans les cellules ciliées auditives - - Usher type I2005 - ANR-05-MRAR-0015 - MRAR - VALID

Subjects
Male, MESH: Cytoskeletal Proteins, [SDV]Life Sciences [q-bio], Cell Cycle Proteins, Plasma protein binding, MESH: Mice, Knockout, MESH: Cadherins, Mice, MESH: Protein Structure, Tertiary, Myosin, MESH: Hair Cells, Auditory, MESH: Animals, Ternary complex, Phospholipids, Genetics (clinical), Mice, Knockout, MESH: Protein Multimerization, Articles, General Medicine, Cadherins, [SDV] Life Sciences [q-bio], Biochemistry, Myosin VIIa, Female, Usher Syndromes, Protein Binding, Gene isoform, PDZ domain, MESH: Carrier Proteins, macromolecular substances, Myosins, Biology, Cell Line, MESH: Cell Cycle Proteins, Hair Cells, Auditory, otorhinolaryngologic diseases, Genetics, Molecular motor, Animals, Humans, MESH: Myosin VIIa, MESH: Protein Binding, MESH: Usher Syndromes, MESH: Mice, Molecular Biology, MESH: Phospholipids, MESH: Humans, Cadherin, MESH: Myosins, MESH: Male, Protein Structure, Tertiary, MESH: Cell Line, Cytoskeletal Proteins, Disease Models, Animal, Cytoplasm, Biophysics, sense organs, Protein Multimerization, MESH: Disease Models, Animal, Carrier Proteins, MESH: Female
Abstract

International audience; Cadherin-23 is a component of early transient lateral links of the auditory sensory cells' hair bundle, the mechanoreceptive structure to sound. This protein also makes up the upper part of the tip links that control gating of the mechanoelectrical transduction channels. We addressed the issue of the molecular complex that anchors these links to the hair bundle F-actin core. By using surface plasmon resonance assays, we show that the cytoplasmic regions of the two cadherin-23 isoforms that do or do not contain the exon68encoded peptide directly interact with harmonin, a submembrane PDZ (post-synaptic density, disc large, zonula occludens) domain-containing protein, with unusually high affinity. This interaction involves the harmonin Nter-PDZ1 supramodule, but not the C-terminal PDZ-binding motif of cadherin-23. We establish that cadherin-23 directly binds to the tail of myosin VIIa. Moreover, cadherin-23, harmonin and myosin VIIa can form a ternary complex, which suggests that myosin VIIa applies tension forces on hair bundle links. We also show that the cadherin-23 cytoplasmic region, harmonin and myosin VIIa interact with phospholipids on synthetic liposomes. Harmonin and the cytoplasmic region of cadherin-23, both independently and as a binary complex, can bind specifically to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2), which may account for the role of this phospholipid in the adaptation of mechanoelectrical transduction in the hair bundle. The distributions of cadherin-23, harmonin, myosin VIIa and PI(4,5)P 2 in the growing and mature auditory hair bundles as well as the abnormal locations of harmonin and myosin VIIa in cadherin-23 null mutant mice strongly support the functional relevance of these interactions.

Published
2010
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4. 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
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5. Four-Year Follow-up of Diagnostic Service in USH1 Patients

Author

Muriel Holder-Espinasse, Albert David, Brigitte Gilbert-Dussardier, Michel Mondain, Mireille Claustres, Christel Vaché, Anne Francoise Roux, Christian P. Hamel, Sue Malcolm, Geneviève Lina-Granade, Didier Lacombe, Umberto Ambrosetti, Thomas Besnard, Susana Léonard, Dominique Bonneau, Catherine Blanchet, Hubert Journel, Valérie Faugère, Patrick Edery, David Baux, 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 d'ORL, Hôpital Gui de Chauliac (CHRU de Montpellier), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service ORL, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier], Service Génétique Médicale [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), GENDEV Team [Bron], Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, 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), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Università degli Studi di Milano [Milano] (UNIMI), CHU Pontchaillou [Rennes], Centre hospitalier universitaire de Nantes (CHU Nantes), 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), Clinical and Molecular Genetics, University College of London [London] (UCL)-Institute of Child Health, Supported in part by le Ministère de la Recherche 'PHRC (Le Programme Hospitalier de Recherche Clinique) National 2004, PROM 7802,' AG2R Foundation, and SOS Rétinite., and The authors thank the families who participated in this study and Clarisse Baumann, Maria Bitner-Glindzicz, Patricia Blanchet, Pierangela Castorina, Christine Francannet, Anne-Marie Frances, Alice Goldenberg, Georges Haddad, Koenraad Devriendt, Sandrine Marlin, Dominique Martin-Coignard, Philippe Parent, Annick Rossi, Sabine Sigaudy, Renaud Touraine, Annick Toutain, and Jacqueline Vigneron for referring patients and Philippe Khau Van Kien and Christophe Béroud for initial design of the CGH array.

Subjects
DNA Mutational Analysis, medicine.disease_cause, Cohort Studies, MESH: Genotype, 0302 clinical medicine, Genotype, Missense mutation, MESH: DNA Mutational Analysis, MESH: Cohort Studies, Genetics, 0303 health sciences, Mutation, medicine.diagnostic_test, MESH: Genetic Testing, Homozygote, MESH: Genetic Heterogeneity, Chromosome Mapping, MESH: Follow-Up Studies, MESH: Usher Syndromes/genetics, 3. Good health, Myosin VIIa, France, Usher Syndromes, MESH: Homozygote, Mutation, Missense, Myosins, Biology, Genetic Heterogeneity, 03 medical and health sciences, medicine, Humans, MESH: Myosin VIIa, MESH: Usher Syndromes/classification, Genetic Testing, Multiplex ligation-dependent probe amplification, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Gene, 030304 developmental biology, Genetic testing, MESH: Mutation, Missense, MESH: Humans, Genetic heterogeneity, Haplotype, MESH: Haplotypes, MESH: Myosins/genetics, MESH: France, Haplotypes, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Mutation, MESH: Usher Syndromes/diagnosis, MESH: Chromosome Mapping, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

International audience; PURPOSE: The purpose of this study was to establish the mutation spectrum of an Usher type I cohort of 61 patients from France and to describe a diagnostic strategy, including a strategy for estimating the pathogenicity of sequence changes.METHODS: To optimize the identification of Usher (USH)-causative mutations, taking into account the genetic heterogeneity, preliminary haplotyping at the five USH1 loci was performed to prioritize the gene to be sequenced, as previously described. Coding exons and flanking intronic sequences were sequenced and, where necessary, semiquantitative PCR and multiplex ligation-dependent probe amplification (MLPA) were performed to detect large genomic rearrangements.RESULTS: Four years ' experience confirms that the chosen approach provides an efficient diagnostic service. Sixty-one patients showed an abnormal genotype in one of the five USH1 genes. Genetic heterogeneity was confirmed, and, although MYO7A remains the major gene, involvement of other genes is considerable. Distribution of missense, splicing, premature termination codons (PTCs; due to point substitution and small deletions/ or insertions), and large genomic alterations was determined among the USH genes and clearly highlights the need to pay special attention to the diagnostic approach and interpretation, depending on the mutated gene.CONCLUSIONS: Over the 4 years of a diagnostic service offering USH1 patient testing, pathogenic genotypes were identified in most cases (>90%). The complexity and heterogeneity of mutations reinforces the need for a comprehensive approach. Because 32% of the mutations are newly described, the results show that a screening strategy based on known mutations would have solved less than 55% of the cases.

Published
2011
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6. Vezatin, a novel transmembrane protein, bridges myosin VIIA to the cadherin-catenins complex

Author

Uwe Wolfrum, Aziz El-Amraoui, Marc Lecuit, Christine Petit, Saaid Safieddine, Isabelle Perfettini, Polonca Küssel-Andermann, Pascale Cossart, Sylvie Nouaille, Génétique des Déficits sensoriels, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Interactions Bactéries-Cellules, Institut Pasteur [Paris], Johannes Gutenberg - Universität Mainz (JGU), This work was supported by grants from the EC (QLG2-CT-1999-00988), Retina-France, A. & M. Suchert and Forschung contra Blindheit-Initiative Usher Syndrome, a C. & J.-P. Bernais donation, Deutsche Forschungsgemeinschaft (Wo 548/3-1/2 and Wo 548/4-1) (U.W.), FAUN-Stiftung, Nürnberg (U.W.) and the Pasteur Weizmann Joint Research Program (P.C.)., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), and Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU)

Subjects
MESH: Cytoskeletal Proteins, MESH: alpha Catenin, Stereocilia (inner ear), [SDV]Life Sciences [q-bio], MESH: Amino Acid Sequence, Deafness, MESH: Cadherins, Mice, MESH: Protein Structure, Tertiary, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Myosin, MESH: Hair Cells, Auditory, MESH: Animals, Cytoskeleton, 0303 health sciences, FERM domain, General Neuroscience, MESH: Alternative Splicing, Articles, Cadherins, Cell biology, medicine.anatomical_structure, Intercellular Junctions, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Myosin VIIa, Hair cell, MESH: Membrane Proteins, MESH: Dyneins, Protein Binding, MESH: Mutation, Macromolecular Substances, Molecular Sequence Data, MESH: Deafness, macromolecular substances, Biology, In Vitro Techniques, Myosins, General Biochemistry, Genetics and Molecular Biology, Cell Line, Adherens junction, 03 medical and health sciences, Hair Cells, Auditory, medicine, otorhinolaryngologic diseases, Animals, Humans, MESH: Myosin VIIa, MESH: Protein Binding, Amino Acid Sequence, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH: In Vitro Techniques, MESH: Molecular Sequence Data, MESH: Humans, General Immunology and Microbiology, Cadherin, Dyneins, Membrane Proteins, MESH: Macromolecular Substances, MESH: Myosins, Actin cytoskeleton, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Protein Structure, Tertiary, MESH: Cell Line, Alternative Splicing, Cytoskeletal Proteins, Mutation, sense organs, 030217 neurology & neurosurgery, alpha Catenin, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, MESH: Intercellular Junctions
Abstract

International audience; Defects in myosin VIIA are responsible for deafness in the human and mouse. The role of this unconventional myosin in the sensory hair cells of the inner ear is not yet understood. Here we show that the C-terminal FERM domain of myosin VIIA binds to a novel transmembrane protein, vezatin, which we identi®ed by a yeast two-hybrid screen. Vezatin is a ubiquitous protein of adherens cell±cell junctions, where it interacts with both myosin VIIA and the cadherin±catenins complex. Its recruitment to adherens junctions implicates the C-terminal region of a-catenin. Taken together, these data suggest that myosin VIIA, anchored by vezatin to the cadherin±catenins complex, creates a tension force between adherens junctions and the actin cytoskeleton that is expected to strengthen cell±cell adhesion. In the inner ear sensory hair cells vezatin is, in addition, concentrated at another membrane±membrane interaction site, namely at the ®brillar links interconnecting the bases of adjacent stereocilia. In myosin VIIA-defective mutants, inactivity of the vezatin±myosin VIIA complex at both sites could account for splaying out of the hair cell stereocilia.

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