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1. Otoferlin acts as a Ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses

Author: Nicolas Michalski, Juan D Goutman, Sarah Marie Auclair, Jacques Boutet de Monvel, Margot Tertrais, Alice Emptoz, Alexandre Parrin, Sylvie Nouaille, Marc Guillon, Martin Sachse, Danica Ciric, Amel Bahloul, Jean-Pierre Hardelin, Roger Bryan Sutton, Paul Avan, Shyam S Krishnakumar, James E Rothman, Didier Dulon, Saaid Safieddine, and Christine Petit
Subjects: deafness, neurotransmitter release, synaptic exocytotic machinery, synaptopathy, temporal precision, inner hair cell, Medicine, Science, Biology (General), QH301-705.5
Abstract: Hearing relies on rapid, temporally precise, and sustained neurotransmitter release at the ribbon synapses of sensory cells, the inner hair cells (IHCs). This process requires otoferlin, a six C2-domain, Ca2+-binding transmembrane protein of synaptic vesicles. To decipher the role of otoferlin in the synaptic vesicle cycle, we produced knock-in mice (Otof Ala515,Ala517/Ala515,Ala517) with lower Ca2+-binding affinity of the C2C domain. The IHC ribbon synapse structure, synaptic Ca2+ currents, and otoferlin distribution were unaffected in these mutant mice, but auditory brainstem response wave-I amplitude was reduced. Lower Ca2+ sensitivity and delay of the fast and sustained components of synaptic exocytosis were revealed by membrane capacitance measurement upon modulations of intracellular Ca2+ concentration, by varying Ca2+ influx through voltage-gated Ca2+-channels or Ca2+ uncaging. Otoferlin thus functions as a Ca2+ sensor, setting the rates of primed vesicle fusion with the presynaptic plasma membrane and synaptic vesicle pool replenishment in the IHC active zone.
Published: 2017
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2. Diversity of the Genes Implicated in Algerian Patients Affected by Usher Syndrome.

Author: Samia Abdi, Amel Bahloul, Asma Behlouli, Jean-Pierre Hardelin, Mohamed Makrelouf, Kamel Boudjelida, Malek Louha, Ahmed Cheknene, Rachid Belouni, Yahia Rous, Zahida Merad, Djamel Selmane, Mokhtar Hasbelaoui, Crystel Bonnet, Akila Zenati, and Christine Petit
Subjects: Medicine, Science
Abstract: Usher syndrome (USH) is an autosomal recessive disorder characterized by a dual sensory impairment affecting hearing and vision. USH is clinically and genetically heterogeneous. Ten different causal genes have been reported. We studied the molecular bases of the disease in 18 unrelated Algerian patients by targeted-exome sequencing, and identified the causal biallelic mutations in all of them: 16 patients carried the mutations at the homozygous state and 2 at the compound heterozygous state. Nine of the 17 different mutations detected in MYO7A (1 of 5 mutations), CDH23 (4 of 7 mutations), PCDH15 (1 mutation), USH1C (1 mutation), USH1G (1 mutation), and USH2A (1 of 2 mutations), had not been previously reported. The deleterious consequences of a missense mutation of CDH23 (p.Asp1501Asn) and the in-frame single codon deletion in USH1G (p.Ala397del) on the corresponding proteins were predicted from the solved 3D-structures of extracellular cadherin (EC) domains of cadherin-23 and the sterile alpha motif (SAM) domain of USH1G/sans, respectively. In addition, we were able to show that the USH1G mutation is likely to affect the binding interface between the SAM domain and USH1C/harmonin. This should spur the use of 3D-structures, not only of isolated protein domains, but also of protein-protein interaction interfaces, to predict the functional impact of mutations detected in the USH genes.
Published: 2016
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3. Whole exome sequencing identifies mutations in Usher syndrome genes in profoundly deaf Tunisian patients.

Author: Zied Riahi, Crystel Bonnet, Rim Zainine, Saida Lahbib, Yosra Bouyacoub, Rym Bechraoui, Jihène Marrakchi, Jean-Pierre Hardelin, Malek Louha, Leila Largueche, Salim Ben Yahia, Moncef Kheirallah, Leila Elmatri, Ghazi Besbes, Sonia Abdelhak, and Christine Petit
Subjects: Medicine, Science
Abstract: Usher syndrome (USH) is an autosomal recessive disorder characterized by combined deafness-blindness. It accounts for about 50% of all hereditary deafness blindness cases. Three clinical subtypes (USH1, USH2, and USH3) are described, of which USH1 is the most severe form, characterized by congenital profound deafness, constant vestibular dysfunction, and a prepubertal onset of retinitis pigmentosa. We performed whole exome sequencing in four unrelated Tunisian patients affected by apparently isolated, congenital profound deafness, with reportedly normal ocular fundus examination. Four biallelic mutations were identified in two USH1 genes: a splice acceptor site mutation, c.2283-1G>T, and a novel missense mutation, c.5434G>A (p.Glu1812Lys), in MYO7A, and two previously unreported mutations in USH1G, i.e. a frameshift mutation, c.1195_1196delAG (p.Leu399Alafs*24), and a nonsense mutation, c.52A>T (p.Lys18*). Another ophthalmological examination including optical coherence tomography actually showed the presence of retinitis pigmentosa in all the patients. Our findings provide evidence that USH is under-diagnosed in Tunisian deaf patients. Yet, early diagnosis of USH is of utmost importance because these patients should undergo cochlear implant surgery in early childhood, in anticipation of the visual loss.
Published: 2015
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4. [Foreword: Chronic diseases: Transition between adolescence to adulthood]

Author: Jean-Pierre, Hardelin
Subjects: Adult, Adolescent, Chronic Disease, Humans, Longitudinal Studies
Published: 2021

5. Avant-propos: Série Maladies chroniques : transition de l’adolescence à l’âge adulte

Author: Jean-Pierre Hardelin, Laboratoire Plasticité du Cerveau Brain Plasticity (UMR 8249) (PdC), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Neurosciences Paris Seine (NPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), and Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-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: 0303 health sciences, medicine.medical_specialty, business.industry, Transition (fiction), [SDV]Life Sciences [q-bio], MEDLINE, General Medicine, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, medicine, Psychiatry, business, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: International audience
Published: 2021
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6. Nicotine inhibits the VTA-to-amygdala dopamine pathway to promote anxiety

Author: Stéphanie Pons, Fabio Marti, Clément Solié, Jean-François Fiancette, Véronique Deroche-Gamonet, Joachim Jehl, Deniz Dalkara, Alexandre Mourot, Jean-Pierre Hardelin, Steve Didienne, Tinaïg Le Borgne, Stefania Tolu, Lauren M. Reynolds, B. Hannesse, Ines Centeno, Uwe Maskos, Sébastien Valverde, Maxime Come, Philippe Faure, Claire Nguyen, Sarah Mondoloni, Romain Durand-de Cuttoli, Laboratoire Plasticité du Cerveau Brain Plasticity (UMR 8249) (PdC), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Neurosciences Paris Seine (NPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-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), Physiopathologie de la Plasticité Neuronale (Neurocentre Magendie - U1215 Inserm), Université de Bordeaux (UB)-Institut François Magendie-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurobiologie intégrative des Systèmes cholinergiques / Integrative Neurobiology of Cholinergic Systems (NISC), Sorbonne Université (SU)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by Centre national de la recherche scientifique (CNRS, UMR 8246), Institut national de la santé et de la recherche médicale (Inserm, U1130), Fondation pour la recherche médicale (FRM, DEQ2013326488 to P.F., FDT201904008060 to S.M., ECO201806006688 to J.J., and SPF202005011922 to C.S.), French National Cancer Institute grants TABAC-16-022 and TABAC-19-020 (to P.F.), French state funds managed by Agence Nationale de la Recherche (ANR-16 Nicostress to P.F., ANR-19 Vampire to F.M.), and LabEx Bio-Psy (to P.F. and a doctoral fellowship to C.N.). L.M.R. was supported by a National Institute on Drug Abuse (NIDA)-Inserm Postdoctoral Drug Abuse Research Fellowship. P.F. and U.M. are members of LabEx Bio-Psy., ANR-16-CE16-0020,nicostress,Réseaux neuronaux sous-tendant l'intéraction entre stress et nicotine dans le cadre des troubles psychiatriques(2016), ANR-19-CE16-0001,VAmPiRe,Effets opposés de la nicotine sur des neurones dopaminergiques distincts : un rôle spécifique de la voie VTA-Amygdala dans le renforcement(2019), ANR-11-LABX-0035,BIOPSY,Laboratoire de Psychiatrie Biologique(2011), Moheb, Tara, Réseaux neuronaux sous-tendant l'intéraction entre stress et nicotine dans le cadre des troubles psychiatriques - - nicostress2016 - ANR-16-CE16-0020 - AAPG2016 - VALID, Effets opposés de la nicotine sur des neurones dopaminergiques distincts : un rôle spécifique de la voie VTA-Amygdala dans le renforcement - - VAmPiRe2019 - ANR-19-CE16-0001 - AAPG2019 - VALID, Laboratoire de Psychiatrie Biologique - - BIOPSY2011 - ANR-11-LABX-0035 - LABX - VALID, Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale (U1215 Inserm - UB), Institut Pasteur [Paris] (IP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, nucleus accumbens, Dopamine, Anxiety, Receptors, Nicotinic, dopamine circuits, MESH: Nicotine, Nicotine, Mice, [SCCO]Cognitive science, 0302 clinical medicine, MESH: Amygdala, Neural Pathways, MESH: Dopaminergic Neurons, MESH: Animals, Nicotinic Agonists, 0303 health sciences, Chemistry, General Neuroscience, musculoskeletal, neural, and ocular physiology, amygdala, Ventral tegmental area, Nicotinic agonist, medicine.anatomical_structure, MESH: Receptors, Nicotinic, addiction, MESH: Nucleus Accumbens, Reinforcement, Psychology, psychological phenomena and processes, medicine.drug, ventral tegmental area, MESH: Dopamine, Nucleus accumbens, Optogenetics, Amygdala, 03 medical and health sciences, mental disorders, MESH: Nicotinic Agonists, medicine, Animals, optogenetics, MESH: Mice, 030304 developmental biology, MESH: Anxiety, Dopaminergic Neurons, MESH: Neural Pathways, [SCCO] Cognitive science, MESH: Male, Anxiogenic, nervous system, juxtacellular recordings, MESH: Ventral Tegmental Area, nicotinic acetylcholine receptors, Neuroscience, MESH: Reinforcement, Psychology, 030217 neurology & neurosurgery, nicotine
Abstract: International audience; Nicotine stimulates dopamine (DA) neurons of the ventral tegmental area (VTA) to establish and maintain reinforcement. Nicotine also induces anxiety through an as yet unknown circuitry. We found that nicotine injection drives opposite functional responses of two distinct populations of VTA DA neurons with anatomically segregated projections: it activates neurons that project to the nucleus accumbens (NAc), whereas it inhibits neurons that project to the amygdala nuclei (Amg). We further show that nicotine mediates anxiety-like behavior by acting on β2-subunit-containing nicotinic acetylcholine receptors of the VTA. Finally, using optogenetics, we bidirectionally manipulate the VTA-NAc and VTA-Amg pathways to dissociate their contributions to anxiety-like behavior. We show that inhibition of VTA-Amg DA neurons mediates anxiety-like behavior, while their activation prevents the anxiogenic effects of nicotine. These distinct subpopulations of VTA DA neurons with opposite responses to nicotine may differentially drive the anxiogenic and the reinforcing effects of nicotine.
Published: 2021
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7. Otogelin, otogelin-like, and stereocilin form links connecting outer hair cell stereocilia to each other and the tectorial membrane

Author: Paul Avan, Sébastien Le Gal, Vincent Michel, Typhaine Dupont, Elisabeth Verpy, Christine Petit, Jean-Pierre Hardelin, Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique et Physiologie de l'Audition, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), This work was supported by the European Commission (ERC-2011-ADG-294570, to C.P.), Banque Nationale de Paris Paribas, Fondation pour l’Audition, Stiftung Lebenshilfewerk, and by French state funds managed by the Agence Nationale de la Recherche within the 'Investissement d’Avenir' program (ANR-15-RHUS-0001 and LabEx LifeSenses ANR-10-LABX-65) and ANR-16-CE13-0015-02., We thank Jacques Boutet de Monvel for helpful comments on the manuscript, and Jérémie Chatel-Poujade, Isabelle Perfettini, and Céline Trébeau for technical assistance., ANR-15-RHUS-0001,LIGHT4DEAF,ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER(2015), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Chaire Génétique et physiologie cellulaire
Subjects: Tectorial Membrane, Tectorial membrane, Hearing Loss, Sensorineural, Stereocilia (inner ear), Mechanoelectrical transduction, horizontal top connector, Deafness, Stereocilia, Hair Cells, Vestibular, Mice, 03 medical and health sciences, 0302 clinical medicine, otoacoustic emission, otorhinolaryngologic diseases, medicine, Animals, Genetic Predisposition to Disease, air bundle link, Outer hair cells, tectorial membrane-attachment crown, Cochlea, 030304 developmental biology, outer hair cell, Mice, Knockout, 0303 health sciences, Membrane Glycoproteins, Multidisciplinary, Chemistry, [SCCO.NEUR]Cognitive science/Neuroscience, Biological Sciences, Cell biology, Sensory epithelium, Hair Cells, Auditory, Outer, medicine.anatomical_structure, Intercellular Signaling Peptides and Proteins, sense organs, Hair cell, 030217 neurology & neurosurgery
Abstract: International audience; The function of outer hair cells (OHCs), the mechanical actuators of the cochlea, involves the anchoring of their tallest stereocilia in the tectorial membrane (TM), an acellular structure overlying the sensory epithelium. Otogelin and otogelin-like are TM proteins related to secreted epithelial mucins. Defects in either cause the DFNB18B and DFNB84B genetic forms of deafness, respectively, both characterized by congenital mild-to-moderate hearing impairment. We show here that mutant mice lacking otogelin or otogelin-like have a marked OHC dysfunction, with almost no acoustic distortion products despite the persistence of some mechanoelectrical transduction. In both mutants, these cells lack the horizontal top connectors, which are fibrous links joining adjacent stereocilia, and the TM-attachment crowns coupling the tallest stereocilia to the TM. These defects are consistent with the previously unrecognized presence of otogelin and otogelin-like in the OHC hair bundle. The defective hair bundle cohesiveness and the absence of stereociliary imprints in the TM observed in these mice have also been observed in mutant mice lacking stereocilin, a model of the DFNB16 genetic form of deafness, also characterized by congenital mild-to-moderate hearing impairment. We show that the localizations of stereocilin, otogelin, and otogelin-like in the hair bundle are interdependent, indicating that these proteins interact to form the horizontal top connectors and the TM-attachment crowns. We therefore suggest that these 2 OHC-specific structures have shared mechanical properties mediating reaction forces to sound-induced shearing motion and contributing to the coordinated displacement of stereocilia.
Published: 2019
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8. Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model

Author: Omar Akil, Saaid Safieddine, Jacques Boutet de Monvel, Charlotte Calvet, Frank M. Dyka, Ghizlene Lahlou, Sylvie Nouaille, Jean-Pierre Hardelin, Paul Avan, Alice Emptoz, Christine Petit, William W. Hauswirth, Lawrence R. Lustig, University of California [San Francisco] (UC San Francisco), University of California (UC), University of Florida [Gainesville] (UF), Génétique et Physiologie de l'Audition, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), ED 515 - Complexité du vivant, Sorbonne Université (SU), Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Columbia University Medical Center (CUMC), Columbia University [New York], This work was supported by the Hearing Research Incorporation (O.A.), Fondation pour la Recherche Médicale (A.E.), Région Ile de France (DIM Thérapie génique), the European Union Seventh Framework Programme under the Grant Agreement HEALTH-F2-2010-242013 (TREAT RUSH), the French government funds managed by Agence Nationale de la Recherche (EargenCure), and LabEx Lifesenses (ANR-10-BNP Paribas Foundation, FAUN Stiftung, LHW Stiftung, and Mrs. Errera Hoechstetter)., ANR-17-CE18-0027,EARGENCURE,Restauration, par thérapie génique, de l'audition et de l'équilibre chez des souris modèles de surdités et troubles vestibulaires humains(2017), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), European Project: 242013,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,TREATRUSH(2010), University of California [San Francisco] (UCSF), University of California, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Chaire Génétique et physiologie cellulaire
Subjects: Medical Sciences, [SDV]Life Sciences [q-bio], Genetic enhancement, Genetic Vectors, Mutant, Mice, Transgenic, Biology, law.invention, Mice, otoferlin, 03 medical and health sciences, 0302 clinical medicine, law, deafness, Complementary DNA, otorhinolaryngologic diseases, DFNB9, Animals, Humans, Coding region, Vector (molecular biology), Gene, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Membrane Proteins, Genetic Therapy, Biological Sciences, Dependovirus, gene therapy, Phenotype, Cell biology, Mice, Inbred C57BL, Disease Models, Animal, Recombinant DNA, dual AAV, 030217 neurology & neurosurgery
Abstract: Significance In humans, inner ear development is completed in utero, with hearing onset at ∼20 weeks of gestation. However, genetic forms of congenital deafness are typically diagnosed during the neonatal period. Gene therapy approaches in animal models should therefore be tested after the period of hearing onset, to determine whether they can reverse an existing deafness phenotype. Here, we used a mouse model of DFNB9, a human deafness form accounting for 2–8% of all cases of congenital genetic deafness. We show that local gene therapy in the mutant mice not only prevents deafness when administered to immature hearing organs, but also durably restores hearing when administered at a mature stage, raising hopes for future gene therapy trials in DFNB9 patients., Autosomal recessive genetic forms (DFNB) account for most cases of profound congenital deafness. Adeno-associated virus (AAV)-based gene therapy is a promising therapeutic option, but is limited by a potentially short therapeutic window and the constrained packaging capacity of the vector. We focus here on the otoferlin gene underlying DFNB9, one of the most frequent genetic forms of congenital deafness. We adopted a dual AAV approach using two different recombinant vectors, one containing the 5′ and the other the 3′ portions of otoferlin cDNA, which exceed the packaging capacity of the AAV when combined. A single delivery of the vector pair into the mature cochlea of Otof−/− mutant mice reconstituted the otoferlin cDNA coding sequence through recombination of the 5′ and 3′ cDNAs, leading to the durable restoration of otoferlin expression in transduced cells and a reversal of the deafness phenotype, raising hopes for future gene therapy trials in DFNB9 patients.
Published: 2019
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9. Vers une thérapie génique de certaines surdités congénitales ?

Author: Jean-Pierre Hardelin and Saaid Safieddine
Subjects: Text mining, business.industry, Hearing loss, Genetic enhancement, medicine, MEDLINE, Historical Article, General Medicine, medicine.symptom, Bioinformatics, business, General Biochemistry, Genetics and Molecular Biology
Published: 2019
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10. Interaction of protocadherin-15 with the scaffold protein whirlin supports its anchoring of hair-bundle lateral links in cochlear hair cells

Author: Elise Pepermans, Vincent Michel, Alain Aghaie, Jean-Pierre Hardelin, Amel Bahloul, Sylvie Nouaille, Isabelle Perfettini, Patrick England, Christine Petit, Jacques Boutet de Monvel, Florent Delhommel, Nicolas Wolff, Génétique et Physiologie de l'Audition, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), ED 515 - Complexité du vivant, Sorbonne Université (SU), Institut de l'Audition [Paris] (IDA), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Biophysique Moléculaire (plateforme) - Molecular Biophysics (platform), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Structural Biology (Neuherberg), Helmholtz-Zentrum München (HZM), Récepteurs Canaux - Channel Receptors, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Stanford University, This work was supported by Institut Pasteur PTR program No.483, by Agence Nationale de la Recherche (ANR) within the framework of the Investissements d'Avenir program (ANR‐15‐RHUS‐0001), Laboratoire d'excellence (LabEx) Lifesenses (ANR‐10‐LABX‐65), ANR‐11‐IDEX‐0004‐02, ANR‐11‐BSV5‐0011, and grants from Fondation Agir pour l'Audition, the BNP Paribas Foundation, the FAUN Stiftung, the LHW‐Stiftung and Mrs. Errera Hoechstetter., ANR-15-RHUS-0001,LIGHT4DEAF,ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER(2015), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), ANR-11-BSV5-0011,EARMEC,Propriétés mécaniques, actives et passives, de la touffe ciliaire des cellules mécano-sensorielles ciliées le long de l'axe tonotopique de la cochlée des mammifères.(2011), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Helmholtz Zentrum München = German Research Center for Environmental Health, Collège de France - Chaire Génétique et physiologie cellulaire, Gestionnaire, HAL Sorbonne Université 5, ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER - - LIGHT4DEAF2015 - ANR-15-RHUS-0001 - RHUS - VALID, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, and BLANC - Propriétés mécaniques, actives et passives, de la touffe ciliaire des cellules mécano-sensorielles ciliées le long de l'axe tonotopique de la cochlée des mammifères. - - EARMEC2011 - ANR-11-BSV5-0011 - BLANC - VALID
Subjects: Scaffold protein, Male, Stereocilia (inner ear), PDZ domain, lcsh:Medicine, Cadherin Related Proteins, Diseases, [SDV.GEN] Life Sciences [q-bio]/Genetics, Mechanotransduction, Cellular, Biochemistry, Article, Stereocilia, 03 medical and health sciences, Mice, 0302 clinical medicine, CDH23, Hair Cells, Auditory, medicine, otorhinolaryngologic diseases, Animals, Protein Isoforms, Protein Precursors, Cytoskeleton, lcsh:Science, 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Multidisciplinary, Chemistry, lcsh:R, Membrane Proteins, Cell Differentiation, Actin cytoskeleton, Cadherins, Cell biology, Cochlea, Mice, Inbred C57BL, medicine.anatomical_structure, Microscopy, Electron, Scanning, lcsh:Q, Female, Hair cell, sense organs, Engineering sciences. Technology, 030217 neurology & neurosurgery, PCDH15, Neuroscience
Abstract: International audience; The hair bundle of cochlear hair cells is the site of auditory mechanoelectrical transduction. It is formed by three rows of stiff microvilli-like protrusions of graduated heights, the short, middle-sized, and tall stereocilia. In developing and mature sensory hair cells, stereocilia are connected to each other by various types of fibrous links. Two unconventional cadherins, protocadherin-15 (PCDH15) and cadherin-23 (CDH23), form the tip-links, whose tension gates the hair cell mechanoelectrical transduction channels. These proteins also form transient lateral links connecting neighboring stereocilia during hair bundle morphogenesis. The proteins involved in anchoring these diverse links to the stereocilia dense actin cytoskeleton remain largely unknown. We show that the long isoform of whirlin (L-whirlin), a PDZ domain-containing submembrane scaffold protein, is present at the tips of the tall stereocilia in mature hair cells, together with PCDH15 isoforms CD1 and CD2; L-whirlin localization to the ankle-link region in developing hair bundles moreover depends on the presence of PCDH15-CD1 also localizing there. We further demonstrate that L-whirlin binds to PCDH15 and CDH23 with moderate-to-high affinities in vitro. From these results, we suggest that L-whirlin is part of the molecular complexes bridging PCDH15-, and possibly CDH23-containing lateral links to the cytoskeleton in immature and mature stereocilia. The sensory cells of the cochlea (inner and outer hair cells) convert acoustic waves into receptor potentials by the process of mechanoelectrical transduction (MET) 1,2. This process takes place in the hair bundle, a mechanosensi-tive antenna formed by thick and stiff microvilli-like protrusions called stereocilia, organized in three rows of graduated height (i.e., short, middle-sized, and tall stereocilia) at the apical surface of the hair cells. Stereocilia are connected, within and between rows, by various types of fibrous links, expressed both in the developing and the mature cochlea. According to the current view of the MET process, cationic transducer channels located at the tips of short and middle-sized stereocilia 3 are gated by the sound-evoked periodic tension of the tip link, an open
Published: 2019
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11. Mutations in CDC14A , Encoding a Protein Phosphatase Involved in Hair Cell Ciliogenesis, Cause Autosomal-Recessive Severe to Profound Deafness

Author: Zied Riahi, Christine Petit, Sébastien Chardenoux, Hala El Hachmi, Crystel Bonnet, Sedigheh Delmaghani, Philippe Herbomel, Isabelle Perfettini, Yosra Bouyacoub, Ahmed Houmeida, Jean-Pierre Hardelin, Asadollah Aghaie, Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), 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), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP), Laboratoire de Biochimie et Biologie Moléculaire [Nouakchott], Faculté des Sciences et Techniques [Nouakchott, Mauritania], Macrophages et Développement de l’Immunité, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), ED 515 - Complexité du vivant, Université Pierre et Marie Curie - Paris 6 (UPMC), This work was supported by the French state program 'Investissements d’Avenir' (ANR-10-LABX-65), BNP Paribas, and Bucodes SurdiFrance., Chaire Génétique et physiologie cellulaire, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and HAL-UPMC, Gestionnaire
Subjects: Adult, Male, 0301 basic medicine, Morpholino, Hearing Loss, Sensorineural, Nonsense mutation, Fluorescent Antibody Technique, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Severity of Illness Index, Mice, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Report, Ciliogenesis, Hair Cells, Auditory, otorhinolaryngologic diseases, Genetics, medicine, Animals, Humans, Genetics(clinical), Cilia, Nonsyndromic deafness, Zebrafish, Genetics (clinical), Aged, [SDV.GEN]Life Sciences [q-bio]/Genetics, Cilium, Middle Aged, Kinocilium, medicine.disease, biology.organism_classification, Molecular biology, Phosphoric Monoester Hydrolases, Pedigree, 030104 developmental biology, medicine.anatomical_structure, Larva, Mutation, Female, sense organs, Hair cell, Protein Tyrosine Phosphatases, 030217 neurology & neurosurgery
Abstract: International audience; By genetic linkage analysis in a large consanguineous Iranian family with eleven individuals affected by severe to profound congenital deafness, we were able to define a 2.8 Mb critical interval (at chromosome 1p21.2-1p21.1) for an autosomal-recessive nonsyndromic deafness locus (DFNB). Whole-exome sequencing allowed us to identify a CDC14A biallelic nonsense mutation, c.1126C>T (p.Arg376∗), which was present in the eight clinically affected individuals still alive. Subsequent screening of 115 unrelated individuals affected by severe or profound congenital deafness of unknown genetic cause led us to identify another CDC14A biallelic nonsense mutation, c.1015C>T (p.Arg339∗), in an individual originating from Mauritania. CDC14A encodes a protein tyrosine phosphatase. Immunofluorescence analysis of the protein distribution in the mouse inner ear showed a strong labeling of the hair cells’ kinocilia. By using a morpholino strategy to knockdown cdc14a in zebrafish larvae, we found that the length of the kinocilia was reduced in inner-ear hair cells. Therefore, deafness caused by loss-of-function mutations in CDC14A probably arises from a morphogenetic defect of the auditory sensory cells’ hair bundles, whose differentiation critically depends on the proper growth of their kinocilium.
Published: 2016
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12. 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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13. Neuroendocrinology right from the nose: Genetics and pathophysiology of the olfacto-genital syndrome (Kallmann syndrome)

Author: Jean-Pierre Hardelin
Subjects: medicine.anatomical_structure, business.industry, Kallmann syndrome, Medicine, Sex organ, Anatomy, Neuroendocrinology, business, medicine.disease, Pathophysiology, Nose
Published: 2018
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14. Author response: Otoferlin acts as a Ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses

Author: Alexandre Parrin, Amel Bahloul, Sylvie Nouaille, Christine Petit, Sarah M. Auclair, Martin Sachse, Nicolas Michalski, Juan D Goutman, Marc Guillon, Didier Dulon, Margot Tertrais, Saaid Safieddine, Danica Ciric, Paul Avan, Roger Bryan Sutton, Jacques Boutet de Monvel, Jean-Pierre Hardelin, Shyam S. Krishnakumar, James E. Rothman, and Alice Emptoz
Subjects: Auditory Hair Cell, Vesicle fusion, Chemistry, Vesicle, Ribbon synapse, Cell biology
Published: 2017
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15. Local gene therapy durably restores vestibular function in a mouse model of Usher syndrome type 1G

Author: Alice, Emptoz, Vincent, Michel, Andrea, Lelli, Omar, Akil, Jacques, Boutet de Monvel, Ghizlene, Lahlou, Anaïs, Meyer, Typhaine, Dupont, Sylvie, Nouaille, Elody, Ey, Filipa, Franca de Barros, Mathieu, Beraneck, Didier, Dulon, Jean-Pierre, Hardelin, Lawrence, Lustig, Paul, Avan, Christine, Petit, Saaid, Safieddine, 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), ED 515 - Complexité du vivant, Université Pierre et Marie Curie - Paris 6 (UPMC), University of California [San Francisco] (UC San Francisco), University of California (UC), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre de neurophysique, physiologie, pathologie (UMR 8119), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Neurophysiologie de la Synapse Auditive, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU de Bordeaux Pellegrin [Bordeaux]-Neuroscience Institute, Columbia University [New York], Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), This work was supported by Fondation pour la Recherche Médicale (A.E.), the European UnionSeventh Framework Programme under the grant agreement HEALTH-F2-2010-242013 (TREATRUSH), the European Commission (ERC-2011-ADG_294570), French state funds managed by Agence Nationale de la Recherche within theInvestissements d’Avenir Programme (ANR-15-RHUS-0001), LabEx Lifesenses(ANR-10-LABX-65), and grants from the BNP Paribas Foundation, the FAUN-Stiftung, the LHW-Stiftung, and Errera Hoechstetter., ANR-15-RHUS-0001,LIGHT4DEAF,ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER(2015), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), European Project: 242013,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,TREATRUSH(2010), European Project: 294570,EC:FP7:ERC,ERC-2011-ADG_20110310,HAIRBUNDLE(2012), CHAUVET, Laurence, ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER - - LIGHT4DEAF2015 - ANR-15-RHUS-0001 - RHUS - VALID, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, Fighting blindness of Usher syndrome: diagnosis, pathogenesis and retinal treatment (TreatRetUsher) - TREATRUSH - - EC:FP7:HEALTH2010-02-01 - 2014-01-31 - 242013 - VALID, Assembling the puzzle of the operating auditory hair bundle - HAIRBUNDLE - - EC:FP7:ERC2012-12-01 - 2017-11-30 - 294570 - VALID, Chaire Génétique et physiologie cellulaire, University of California [San Francisco] (UCSF), University of California, Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)
Subjects: DNA, Complementary, [SDV]Life Sciences [q-bio], Genetic Vectors, Nerve Tissue Proteins, Mice, Hair Cells, Auditory, Evoked Potentials, Auditory, Brain Stem, otorhinolaryngologic diseases, Animals, Humans, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, gene, mouse, Mice, Knockout, therapy, balance, Genetic Therapy, Dependovirus, Biological Sciences, [SDV] Life Sciences [q-bio], Disease Models, Animal, Animals, Newborn, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Microscopy, Electron, Scanning, Vestibule, Labyrinth, sense organs, Usher Syndromes, Usher
Abstract: International audience; Our understanding of the mechanisms underlying inherited forms of inner ear deficits has considerably improved during the past 20 y, but we are still far from curative treatments. We investigated gene replacement as a strategy for restoring inner ear functions in a mouse model of Usher syndrome type 1G, characterized by congenital profound deafness and balance disorders. These mice lack the scaffold protein sans, which is involved both in the morphogenesis of the stereociliary bundle, the sensory antenna of inner ear hair cells, and in the mechanoelectrical transduction process. We show that a single delivery of the sans cDNA by the adenoassociated virus 8 to the inner ear of newborn mutant mice reestablishes the expression and targeting of the protein to the tips of stereocilia. The therapeutic gene restores the architecture and mechanosensi-tivity of stereociliary bundles, improves hearing thresholds, and durably rescues these mice from the balance defects. Our results open up new perspectives for efficient gene therapy of cochlear and vestibular disorders by showing that even severe dysmorphogenesis of stereociliary bundles can be corrected. gene | therapy | balance | mouse | Usher
Published: 2017
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16. Defective signaling through plexin-A1 compromises the development of the peripheral olfactory system and neuroendocrine reproductive axis in mice

Author: Jean-Pierre Hardelin, Corinne Fouveaut, Catherine Dodé, Fabrice Ango, Séverine Marcos, Nelly Pitteloud, Xavier Rovira, Carine Monnier, Universitat de Vic - Universitat Central de Catalunya. Grup de recerca en Reparació i Regeneració Tissular (TR2Lab), Génétique, physiopathologie et approches thérapeutiques des maladies héréditaires du système nerveux (EA 7331), Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institut Pasteur [Paris], Agence Nationale pour la Recherche (grant number ANR-14-CE12-0015 to S.M., C.M., F.A., C.D., and J.-P.H.), We thank the patients for their contribution to the study. We also thank the animal platform (CRP2, CNRS UMS3612, Inserm US25, Paris-Descartes University) for housing of the mice., ANR-14-CE12-0015,RoSes and GnRH,La signalisation cellulaire par les sémaphorines dans le contrôle neuroendocrinien de la reproduction(2014), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), and CHU Cochin [AP-HP]
Subjects: Male, 0301 basic medicine, Olfactory system, Kallmann syndrome, [SDV]Life Sciences [q-bio], Semaphorins, Gonadotropin-releasing hormone, medicine.disease_cause, Gonadotropin-Releasing Hormone, Mice, 0302 clinical medicine, Cell Movement, Genetics (clinical), Neurons, Mutation, Genètica humana, biology, Reproduction, Oligogenic Inheritance, General Medicine, Olfactory Bulb, 3. Good health, Female, Síndrome de Kallmann, Signal Transduction, Adult, Heterozygote, medicine.medical_specialty, Cell signaling, Hypothalamus, Nerve Tissue Proteins, Receptors, Cell Surface, 03 medical and health sciences, Neuroendocrine Cells, Semaphorin, Internal medicine, Genetics, medicine, Animals, Humans, Molecular Biology, Hypogonadism, Plexin, Semaphorin-3A, Kallmann Syndrome, medicine.disease, 030104 developmental biology, Endocrinology, biology.protein, 030217 neurology & neurosurgery
Abstract: The olfacto-genital syndrome (Kallmann syndrome) associates congenital hypogonadism due to gonadotropin-releasing hormone (GnRH) deficiency and anosmia. This is a genetically heterogeneous developmental disease with various modes of transmission, including oligogenic inheritance. Previous reports have involved defective cell signaling by semaphorin-3A in the disease pathogenesis. Here, we report that the embryonic phenotype of Plxna1-/- mutant mice lacking plexin-A1 (a major receptor of class 3 semaphorins), though not fully penetrant, resembles that of Kallmann syndrome fetuses. Pathohistological analysis indeed showed a strongly abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the hypothalamic brain region in some of the mutant mice, which resulted in reduced fertility in adult males. We thus screened 250 patients for the presence of mutations in PLXNA1, and identified different nonsynonymous mutations (p.V349L, p.V437L, p.R528W, p.H684Y, p.G720E, p.R740H, p.R813H, p.R840Q, p.A854T, p.R897H, p.L1464V, p.K1618T, p.C1744F), all at heterozygous state, in 15 patients. Most of these mutations are predicted to affect plexin-A1 stability or signaling activity based on predictive algorithms and a structural model of the protein. Moreover, in vitro experiments allowed us to show the existence of deleterious effects of eight mutations (including a transcript splicing defect), none of which are expected to result in a complete loss of protein synthesis, targeting, or signaling activity, though. Our findings indicate that signaling insufficiency through plexin-A1 can contribute to the pathogenesis of Kallmann syndrome, and further substantiate the oligogenic pattern of inheritance in this developmental disorder.
Published: 2017
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17. An innovative strategy for the molecular diagnosis of Usher syndrome identifies causal biallelic mutations in 93% of European patients

Author: Christine Petit, Eberhart Zrenner, Shzeena Dad, Martina Jarc-Vidmar, Maria Antonia Claveria, Alberto Auricchio, Ana Fakin, Marko Hawlina, Gaelle M. Lefèvre, Susanne Kohl, Anne Kurtenbach, Aziz El-Amraoui, Loreto Martorell Sampol, Jesus Rodriguez Jorge, Ditta Zobor, Saddek Mohand-Said, Crystel Bonnet, Ieva Sliesoraityte, Charles Marcaillou, Francesco Testa, Saba Battelino, Jaume Mora, Mélanie Letexier, José-Alain Sahel, Francesca Simonelli, Lisbeth Birk Møller, Sandra Chantot-Bastaraud, Jean-Pierre Hardelin, Isabelle Audo, Zied Riahi, Andrej Zupan, Luce Smagghe, Amrit Singh-Estivalet, Damjan Glavač, Souad Gherbi, Sandro Banfi, Sandrine Marlin, 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), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), IntegraGen SA, 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), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), University of Tuebingen, Centre de référence des Surdités Génétiques [CHU Necker, Paris], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Naples Federico II = Università degli studi di Napoli Federico II, Telethon Institute of Genetics and Medicine = Istituto Telethon di Genetica e Medicina (TIGEM), Seconda Università degli Studi di Napoli = Second University of Naples, University Medical Centre Ljubljana [Ljubljana, Slovenia] (UMCL), University of Ljubljana, Hospital Sant Joan de Déu [Barcelona], Kennedy Center, Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), This work was supported by the European Union Seventh Framework Programme under the grant agreement HEALTH-F2-2010-242013 (TREATRUSH), ANR-15-RHUS-001 (LIGHT4DEAF), LHW-Stiftung, Fondation Raymonde & Guy Strittmatter, FAUN Stiftung, Conny Maeva Charitable Foundation, Fondation Orange, Fondation BNP Paribas, LABEX Lifesenses [ANR-10-LABX-65], 'the Foundation Fighting Blindness Paris Center Grant', and the Slovenian research agency (ARRS P3-0333)., We are grateful to the patients and their families for their participation in the study. DNA samples included in this study originated from the NeuroSensCol** DNA bank, part of the BioCollections network for research in neuroscience (PI: JA Sahel, co-PI: I Audo, in partnership with the CHNO des Quinze-Vingts, Inserm and the CNRS), and the Tuebingen RetDis biobank (PI: B Wissinger, co-PI S Kohl)., ANR-15-RHUS-0001,LIGHT4DEAF,ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER(2015), ANR-10-LABX-0065,LIFESENSES,DES SENS POUR TOUTE LA VIE(2010), European Project: 242013,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,TREATRUSH(2010), Bonnet, Crystel, ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER - - LIGHT4DEAF2015 - ANR-15-RHUS-0001 - RHUS - VALID, DES SENS POUR TOUTE LA VIE - - LIFESENSES2010 - ANR-10-LABX-0065 - LABX - VALID, Fighting blindness of Usher syndrome: diagnosis, pathogenesis and retinal treatment (TreatRetUsher) - TREATRUSH - - EC:FP7:HEALTH2010-02-01 - 2014-01-31 - 242013 - VALID, Riahi, Zied, Chantot Bastaraud, Sandra, Smagghe, Luce, Letexier, Mélanie, Marcaillou, Charle, Lefèvre, Gaëlle M, Hardelin, Jean Pierre, El Amraoui, Aziz, Singh Estivalet, Amrit, Mohand Saïd, Saddek, Kohl, Susanne, Kurtenbach, Anne, Sliesoraityte, Ieva, Zobor, Ditta, Gherbi, Souad, Testa, Francesco, Simonelli, Francesca, Banfi, Sandro, Fakin, Ana, Glavač, Damjan, Jarc Vidmar, Martina, Zupan, Andrej, Battelino, Saba, Martorell Sampol, Loreto, Claveria, Maria Antonia, Catala Mora, Jaume, Dad, Shzeena, Møller, Lisbeth B, Rodriguez Jorge, Jesu, Hawlina, Marko, Auricchio, Alberto, Sahel, José Alain, Marlin, Sandrine, Zrenner, Eberhart, Audo, Isabelle, Petit, Christine, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de référence des Surdités Génétiques, University of Naples Federico II, Seconda Università degli studi di Napoli, and Chaire Génétique et physiologie cellulaire
Subjects: 0301 basic medicine, MESH: Extracellular Matrix Proteins, MESH: Sequence Analysis, DNA, Usher syndrome, [SDV]Life Sciences [q-bio], Bioinformatics, 0302 clinical medicine, Exome, Exome sequencing, Genetics (clinical), Genetics, Comparative Genomic Hybridization, Extracellular Matrix Proteins, MESH: Exome, medicine.diagnostic_test, MESH: Genetic Testing, 3. Good health, Europe, [SDV] Life Sciences [q-bio], Medical genetics, MESH: Genes, Modifier, Usher Syndromes, medicine.medical_specialty, MESH: Mutation, Genetic counseling, Biology, Sensitivity and Specificity, Article, 03 medical and health sciences, Molecular genetics, medicine, otorhinolaryngologic diseases, Humans, Genetic Testing, MESH: Usher Syndromes, Alleles, Genetic testing, Genes, Modifier, MESH: Humans, Genetic heterogeneity, MESH: Alleles, Sequence Analysis, DNA, medicine.disease, MESH: Sensitivity and Specificity, MESH: Comparative Genomic Hybridization, 030104 developmental biology, Mutation, 030221 ophthalmology & optometry, MESH: Europe
Abstract: International audience; Usher syndrome (USH), the most prevalent cause of hereditary deafness-blindness, is an autosomal recessive and genetically heterogeneous disorder. Three clinical subtypes (USH1-3) are distinguishable based on the severity of the sensorineural hearing impairment, the presence or absence of vestibular dysfunction, and the age of onset of the retinitis pigmentosa. A total of 10 causal genes, 6 for USH1, 3 for USH2, and 1 for USH3, and an USH2 modifier gene, have been identified. A robust molecular diagnosis is required not only to improve genetic counseling, but also to advance gene therapy in USH patients. Here, we present an improved diagnostic strategy that is both cost- and time-effective. It relies on the sequential use of three different techniques to analyze selected genomic regions: targeted exome sequencing, comparative genome hybridization, and quantitative exon amplification. We screened a large cohort of 427 patients (139 USH1, 282 USH2, and six of undefined clinical subtype) from various European medical centers for mutations in all USH genes and the modifier gene. We identified a total of 421 different sequence variants predicted to be pathogenic, about half of which had not been previously reported. Remarkably, we detected large genomic rearrangements, most of which were novel and unique, in 9% of the patients. Thus, our strategy led to the identification of biallelic and monoallelic mutations in 92.7% and 5.8% of the USH patients, respectively. With an overall 98.5% mutation characterization rate, the diagnosis efficiency was substantially improved compared with previously reported methods.
Published: 2016
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18. Diversity of the Genes Implicated in Algerian Patients Affected by Usher Syndrome

Author: Amel Bahloul, Zahida Merad, Yahia Rous, Christine Petit, Mokhtar Hasbelaoui, Jean-Pierre Hardelin, Kamel Boudjelida, Akila Zenati, Ahmed Cheknene, Rachid Belouni, Malek Louha, Crystel Bonnet, Samia Abdi, Asma Behlouli, Mohamed Makrelouf, Djamel Selmane, Université Saâd Dahlab Blida 1 (UB1), Université d'Alger, Centre Hospitalo-Universitaire de Blida (CHU Blida), Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Université des Sciences et de la Technologie Houari Boumediene = University of Sciences and Technology Houari Boumediene [Alger] (USTHB), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Bab-el-Oued, Centre Hospitalier Universitaire de Bab-el-Oued, Alger, Algérie., Service ORL [Tizi Ouzou], Centre Hospitalier Universitaire Mohamed Nedir, 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), HAL UPMC, Gestionnaire, Service de Biochimie et de Biologie Moléculaire [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Saâd Dahlab [Blida] (USDB ), Chaire Génétique et physiologie cellulaire, and Université des Sciences et de la Technologie Houari Boumediene [Alger] (USTHB)
Subjects: 0301 basic medicine, Usher syndrome, Gene Identification and Analysis, lcsh:Medicine, Otology, [SDV.GEN] Life Sciences [q-bio]/Genetics, Deafness, 030105 genetics & heredity, medicine.disease_cause, Compound heterozygosity, Biochemistry, Database and Informatics Methods, Medicine and Health Sciences, Missense mutation, lcsh:Science, Hearing Disorders, Genetics, Mutation, Multidisciplinary, Nonsense Mutation, Genomics, Genomic Databases, 3. Good health, Deletion Mutation, Usher Syndromes, Research Article, Missense Mutation, Nonsense mutation, Mutation, Missense, Biology, Research and Analysis Methods, Frameshift mutation, 03 medical and health sciences, Protein Domains, medicine, otorhinolaryngologic diseases, Humans, Genetic Predisposition to Disease, Mutation Detection, [SDV.GEN]Life Sciences [q-bio]/Genetics, Point mutation, lcsh:R, Genetic Variation, Biology and Life Sciences, Proteins, Computational Biology, Genome Analysis, medicine.disease, Biological Databases, Otorhinolaryngology, Algeria, Mutation Databases, lcsh:Q, PCDH15
Abstract: International audience; Usher syndrome (USH) is an autosomal recessive disorder characterized by a dual sensory impairment affecting hearing and vision. USH is clinically and genetically heterogeneous. Ten different causal genes have been reported. We studied the molecular bases of the disease in 18 unrelated Algerian patients by targeted-exome sequencing, and identified the causal biallelic mutations in all of them: 16 patients carried the mutations at the homozygous state and 2 at the compound heterozygous state. Nine of the 17 different mutations detected in MYO7A (1 of 5 mutations), CDH23 (4 of 7 mutations), PCDH15 (1 mutation), USH1C (1 mutation), USH1G (1 mutation), and USH2A (1 of 2 mutations), had not been previously reported. The deleterious consequences of a missense mutation of CDH23 (p. Asp1501Asn) and the in-frame single codon deletion in USH1G (p.Ala397del) on the corresponding proteins were predicted from the solved 3D-structures of extracellular cadherin (EC) domains of cadherin-23 and the sterile alpha motif (SAM) domain of USH1G/sans, respectively. In addition, we were able to show that the USH1G mutation is likely to affect the binding interface between the SAM domain and USH1C/harmonin. This should spur the use of 3D-structures, not only of isolated protein domains, but also of protein-protein interaction interfaces, to predict the functional impact of mutations detected in the USH genes.
Published: 2016
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19. FGFR1, FGF8, PROKR2, PROK2, ANOS1, and the Olfactogenital (Kallmann) Syndrome

Author: Catherine Dodé and Jean-Pierre Hardelin
Subjects: Pediatrics, medicine.medical_specialty, business.industry, Kallmann syndrome, Fibroblast growth factor receptor 1, Medicine, business, medicine.disease
Published: 2016
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20. A novel biallelic splice site mutation of TECTA causes moderate to severe hearing impairment in an Algerian family

Author: Akila Zenati, Mokhtar Hasbellaoui, Jean-Pierre Hardelin, Fatima Ammar-Khodja, Christine Petit, Malek Louha, Farid Boudjenah, Crystel Bonnet, Asma Behlouli, Mohamed Makrelouf, Samia Abdi, Laboratoire de Biochimie Génétique, CHU de Bab El Oued-Université d'Alger 1, Dpt de Biologie et Physiologie des Organismes [Alger], Université des Sciences et de la Technologie Houari Boumediene = University of Sciences and Technology Houari Boumediene [Alger] (USTHB), 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), Laboratoire central de biologie, Université Saâd Dahlab Blida 1 (UB1), Service ORL [Tizi Ouzou], Centre Hospitalier Universitaire Mohamed Nedir, Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), HAL-UPMC, Gestionnaire, Service de Biochimie et de Biologie Moléculaire [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université des Sciences et de la Technologie Houari Boumediene [Alger] (USTHB), Université de Saâd Dahlab [Blida] (USDB ), and Chaire Génétique et physiologie cellulaire
Subjects: 0301 basic medicine, Male, Heterozygote, Hearing Loss, Sensorineural, Consanguinity, 030105 genetics & heredity, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, GPI-Linked Proteins, congenital deafness, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, otorhinolaryngologic diseases, Medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Allele, TECTA, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Child, Exome sequencing, Alleles, Genetics, Extracellular Matrix Proteins, Splice site mutation, Genetic heterogeneity, business.industry, Homozygote, Whole exome sequencing, Heterozygote advantage, General Medicine, 3. Good health, Pedigree, 030104 developmental biology, Otorhinolaryngology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Algeria, Pediatrics, Perinatology and Child Health, Mutation (genetic algorithm), Mutation, Female, RNA Splice Sites, business
Abstract: International audience; Congenital deafness is certainly one of the most common monogenic diseases in humans, but it is also one of the most genetically heterogeneous, which makes molecular diagnosis challenging in most cases. Whole-exome sequencing in two out of three Algerian siblings affected by recessively-inherited, moderate to severe sensorineural deafness allowed us to identify a novel splice donor site mutation (c.5272+1G>A) in the gene encoding α-tectorin, a major component of the cochlear tectorial membrane. The mutation was present at the homozygous state in the three affected siblings, and at the heterozygous state in their unaffected, consanguineous parents. To our knowledge, this is the first reported TECTA mutation leading to the DFNB21 form of hearing impairment among Maghrebian individuals suffering from congenital hearing impairment, which further illustrates the diversity of the genes involved in congenital deafness in the Maghreb.
Published: 2016
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21. Hypervulnerability to Sound Exposure through Impaired Adaptive Proliferation of Peroxisomes

Author: Sylvie Dartevelle, Asadollah Aghaie, Maryline Beurg, E. Sylvester Vizi, Sedigheh Delmaghani, Isabelle Perfettini, Jean Pierre Hardelin, Nicolas Thelen, Alice Emptoz, Guillaume Soubigou, Máté Aller, Didier Dulon, Michel Leibovici, Marc Thiry, Christine Petit, Fabrice Giraudet, Anaïs Meyer, Paul Avan, Tibor Zelles, Saaid Safieddine, Jean Defourny, Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Syndrome de Usher et autres atteintes rétino-cochléaires, 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)-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 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), Neurophysiologie de la Synapse Auditive, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU de Bordeaux Pellegrin [Bordeaux]-Neuroscience Institute, Unit of Cell and Tissue Biology, GIGA-Neurosciences, Université de Liège-CHU Sart Tilman, Institute of Experimental Medicine [Budapest] (KOKI), Hungarian Academy of Sciences (MTA), Department of Pharmacology and Pharmacotherapy, Semmelweis University [Budapest], Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ingénierie des Anticorps (plate-forme) - Antibody Engineering (Platform), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Transcriptome et Epigénome (PF2), Institut Pasteur [Paris] (IP), This work was supported by the Louis-Jeantet Foundation, ANR-NKTH 'HearDeafTrheareat' (2010-INTB-1402-23 01 and TÉT_10-1-2011- 0421), Fondation Bettencourt Schueller, Fondation Agir pour l’Audition, Humanis Novalis- Taitbout, Réunica-Prévoyance, BNP Paribas, and the French state program ‘‘Investissements d’Avenir’’ (ANR-10-LABX-65) (to C.P.)., ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), ANR-10-INTB-0002,HearDeafTreat,Audition et surdité: Mécanismes moléculaires et approches thérapeutiques(2010), Petit, Christine, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, Audition et surdité: Mécanismes moléculaires et approches thérapeutiques - - HearDeafTreat2010 - ANR-10-INTB-0002 - Blanc international 2010 - VALID, 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), ED 515 - Complexité du vivant, Université Pierre et Marie Curie - Paris 6 (UPMC), This work was supported by the Louis-Jeantet Foundation, Fondation BettencourtSchueller, Fondation Agir pour l’Audition, Humanis Novalis-Taitbout, Reunica-Pre´ voyance, BNP Paribas, Chaire Génétique et physiologie cellulaire, CHU Sart Tilman-Université de Liège, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and Institut Pasteur [Paris]
Subjects: Auditory Pathways, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Peroxisome Proliferation, Stimulation, Nerve Tissue Proteins, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, medicine.disease_cause, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Sound exposure, Mice, 0302 clinical medicine, Transcription (biology), Hair Cells, Auditory, medicine, Peroxisomes, otorhinolaryngologic diseases, Auditory system, Animals, Humans, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, 030304 developmental biology, Mice, Knockout, Neurons, 0303 health sciences, Biochemistry, Genetics and Molecular Biology(all), fungi, Proteins, food and beverages, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Anatomy, Peroxisome, Phenotype, Cell biology, Oxidative Stress, medicine.anatomical_structure, Hearing Loss, Noise-Induced, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, 030217 neurology & neurosurgery, Oxidative stress
Abstract: International audience; A deficiency in pejvakin, a protein of unknown function, causes a strikingly heterogeneous form of human deafness. Pejvakin-deficient (Pjvk(-/-)) mice also exhibit variable auditory phenotypes. Correlation between their hearing thresholds and the number of pups per cage suggest a possible harmful effect of pup vocalizations. Direct sound or electrical stimulation show that the cochlear sensory hair cells and auditory pathway neurons of Pjvk(-/-) mice and patients are exceptionally vulnerable to sound. Subcellular analysis revealed that pejvakin is associated with peroxisomes and required for their oxidative-stress-induced proliferation. Pjvk(-/-) cochleas display features of marked oxidative stress and impaired antioxidant defenses, and peroxisomes in Pjvk(-/-) hair cells show structural abnormalities after the onset of hearing. Noise exposure rapidly upregulates Pjvk cochlear transcription in wild-type mice and triggers peroxisome proliferation in hair cells and primary auditory neurons. Our results reveal that the antioxidant activity of peroxisomes protects the auditory system against noise-induced damage.
Published: 2015
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22. EPS8L2 is a new causal gene for childhood onset autosomal recessive progressive hearing loss

Author: Hassina Ibrahim, Gaelle M. Lefèvre, Malika Dahmani, Zahia Mallek, Jean-Pierre Hardelin, Fatima Ammar-Khodja, Crystel Bonnet, Christine Petit, Université des Sciences et de la Technologie Houari Boumediene [Alger] (USTHB), Syndrome de Usher et autres atteintes rétino-cochléaires, 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)-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), Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), ED 515 - Complexité du vivant, Université Pierre et Marie Curie - Paris 6 (UPMC), centre hospitalo-universitaire Mustapha Pacha d'Alger (CHUMA), Centre Hospitalier Universitaire de Bab-el-Oued, Centre Hospitalier Universitaire de Bab-el-Oued, Alger, Algérie., Université des Sciences et de la Technologie Houari Boumediene = University of Sciences and Technology Houari Boumediene [Alger] (USTHB), 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 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), Collège de France - Chaire Génétique et physiologie cellulaire, and Administateur, HAL Sorbonne Université
Subjects: Male, Progressive deafness, Hearing loss, Genes, Recessive, Consanguinity, Biology, Connexins, Frameshift mutation, 03 medical and health sciences, medicine, otorhinolaryngologic diseases, Humans, Genetics(clinical), Pharmacology (medical), Sibling, Child, Frameshift Mutation, Hearing Loss, 10. No inequality, Gene, Exome, Genetics (clinical), Exome sequencing, 030304 developmental biology, Medicine(all), Genetics, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Epidermal growth factor receptor pathway Substrate 8 L2 (EPS8L2), Research, Microfilament Proteins, 030305 genetics & heredity, Membrane Proteins, General Medicine, Human genetics, Pedigree, 3. Good health, Connexin 26, Whole-exome sequencing, Disease Progression, Female, medicine.symptom, Stereocilia bundle, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Background: More than 70 % of the cases of congenital deafness are of genetic origin, of which approximately 80 % are non-syndromic and show autosomal recessive transmission (DFNB forms). To date, 60 DFNB genes have been identified, most of which cause congenital, severe to profound deafness, whereas a few cause delayed progressive deafness in childhood. We report the study of two Algerian siblings born to consanguineous parents, and affected by progressive hearing loss. Method: After exclusion of GJB2 (the gene most frequently involved in non-syndromic deafness in Mediterranean countries), we performed whole-exome sequencing in one sibling. Results: A frame-shift variant (c.1014delC; p.Ser339Alafs*15) was identified in EPS8L2, encoding Epidermal growth factor receptor Pathway Substrate 8 L2, a protein of hair cells' stereocilia previously implicated in progressive deafness in the mouse. This variant predicts a truncated, inactive protein, or no protein at all owing to nonsense-mediated mRNA decay. It was detected at the homozygous state in the two clinically affected siblings, and at the heterozygous state in the unaffected parents and one unaffected sibling, whereas it was never found in a control population of 150 Algerians with normal hearing or in the Exome Variant Server database. Conclusion: Whole-exome sequencing allowed us to identify a new gene responsible for childhood progressive hearing loss transmitted on the autosomal recessive mode.
Published: 2015
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23. Whole exome sequencing identifies mutations in Usher syndrome genes in profoundly deaf Tunisian patients

Author: Sonia Abdelhak, Zied Riahi, L. Largueche, Rim Zainine, Moncef Kheirallah, Leila Elmatri, Christine Petit, Ghazi Besbes, Saida Lahbib, Yosra Bouyacoub, J. Marrakchi, Crystel Bonnet, Jean-Pierre Hardelin, Salim Ben Yahia, Rym Bechraoui, Malek Louha, Laboratoire de Génomique Biomédicale et Oncogénétique - Biomedical Genomics and Oncogenetics Laboratory (LR11IPT05), Université de Tunis El Manar (UTM)-Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP), University of Tunis El Manar, 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), Otorhinolaryngology Diseases, Hôpital La Rabta [Tunis], Université de Monastir - University of Monastir (UM), Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de recherche d'oculogénétique, Service B, Institut Hedi Rais d'ophtalmologie, Department of Ophthalmology, CHU Fattouma Bourguiba [Monastir] (HFB), This work was supported by the Tunisian Ministry of Public Health, the Ministry of Higher Education and Scientific Research (LR11IPT05), the E.C. Grant agreement N° 295097 for FP7 project GM-NCD-Inco (www.genomedika.org), ZR is recipient of a Mobidoc Fellowship under the Programme d’Appui au Système de recherche et d’Innovation (PASRI-Europe Aid) and BNP Paribas foundation., European Project: 295097,EC:FP7:INCO,FP7-INCO-2011-6,GM_NCD_IN_CO(2011), Université de Tunis - El Manar II, Université de Tunis El Manar (UTM), Chaire Génétique et physiologie cellulaire, Oficjalska, Danuta, and Reinforcing IPT capacities in Genomic Medicine, Non Communicable Diseases Investigation and international cooperation - GM_NCD_IN_CO - - EC:FP7:INCO2011-12-01 - 2014-11-30 - 295097 - VALID
Subjects: Male, Tunisia, Genotype, Usher syndrome, Nonsense mutation, lcsh:Medicine, Deafness, Myosins, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Connexins, Retina, Frameshift mutation, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Retinitis pigmentosa, medicine, otorhinolaryngologic diseases, Humans, Missense mutation, Exome, Family, lcsh:Science, Exome sequencing, Genetics, Multidisciplinary, lcsh:R, High-Throughput Nucleotide Sequencing, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, eye diseases, Pedigree, 3. Good health, Connexin 26, Phenotype, Mutation, Anticipation (genetics), [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, lcsh:Q, Genome-Wide Association Study, Research Article
Abstract: International audience; Usher syndrome (USH) is an autosomal recessive disorder characterized by combined deafness-blindness. It accounts for about 50% of all hereditary deafness blindness cases. Three clinical subtypes (USH1, USH2, and USH3) are described, of which USH1 is the most severe form, characterized by congenital profound deafness, constant vestibular dysfunction, and a prepubertal onset of retinitis pigmentosa. We performed whole exome sequencing in four unrelated Tunisian patients affected by apparently isolated, congenital profound deafness, with reportedly normal ocular fundus examination. Four biallelic mutations were identified in two USH1 genes: a splice acceptor site mutation, c.2283-1G>T, and a novel missense mutation, c.5434G>A (p.Glu1812Lys), in MYO7A, and two previously unreported mutations in USH1G, i.e. a frameshift mutation, c.1195_1196delAG (p.Leu399Alafs*24), and a nonsense mutation, c.52A>T (p.Lys18*). Another ophthalmological examination including optical coherence tomography actually showed the presence of retinitis pigmentosa in all the patients. Our findings provide evidence that USH is under-diagnosed in Tunisian deaf patients. Yet, early diagnosis of USH is of utmost importance because these patients should undergo cochlear implant surgery in early childhood, in anticipation of the visual loss.
Published: 2015
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24. Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment

Author: Ulrich, Boehm, Pierre-Marc, Bouloux, Mehul T, Dattani, Nicolas, de Roux, Catherine, Dodé, Leo, Dunkel, Andrew A, Dwyer, Paolo, Giacobini, Jean-Pierre, Hardelin, Anders, Juul, Mohamad, Maghnie, Nelly, Pitteloud, Vincent, Prevot, Taneli, Raivio, Manuel, Tena-Sempere, Richard, Quinton, and Jacques, Young
Subjects: Europe, Gonadotropin-Releasing Hormone, Male, Consensus, Hypogonadism, Humans, Female, Sexual Maturation
Abstract: Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder caused by the deficient production, secretion or action of gonadotropin-releasing hormone (GnRH), which is the master hormone regulating the reproductive axis. CHH is clinically and genetically heterogeneous, with25 different causal genes identified to date. Clinically, the disorder is characterized by an absence of puberty and infertility. The association of CHH with a defective sense of smell (anosmia or hyposmia), which is found in ∼50% of patients with CHH is termed Kallmann syndrome and results from incomplete embryonic migration of GnRH-synthesizing neurons. CHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty. A timely diagnosis and treatment to induce puberty can be beneficial for sexual, bone and metabolic health, and might help minimize some of the psychological effects of CHH. In most cases, fertility can be induced using specialized treatment regimens and several predictors of outcome have been identified. Patients typically require lifelong treatment, yet ∼10-20% of patients exhibit a spontaneous recovery of reproductive function. This Consensus Statement summarizes approaches for the diagnosis and treatment of CHH and discusses important unanswered questions in the field.
Published: 2015

25. Prolonged nicotine exposure reduces aversion to the drug in mice by altering nicotinic transmission in the interpeduncular nucleus.

Author: Mondoloni, Sarah, Nguyen, Claire, Vicq, Eléonore, Ciscato, Maria, Jehl, Joachim, Cuttoli, Romain Durand-de, Torquet, Nicolas, Tolu, Stefania, Pons, Stéphanie, Maskos, Uwe, Marti, Fabio, Faure, Philippe, and Mourot, Alexandre
Published: 2023
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26. D'un protocole de soin au succès d'un essai clinique: Iccarre, QUATUOR, et Jacques Leibowitch.

Author: Petit, Caroline
Published: 2022
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27. Strategies Used by Musicians to Identify Notes' Pitch: Cognitive Bricks and Mental Representations.

Author: Letailleur, Alain, Bisesi, Erica, and Legrain, Pierre
Subjects: MENTAL representation, MUSICAL pitch, MUSICIANS, BRICKS, MUSIC students, STATISTICS, SENSORY perception
Abstract: To this day, the study of the substratum of thought and its implied mechanisms is rarely directly addressed. Nowadays, systemic approaches based on introspective methodologies are no longer fashionable and are often overlooked or ignored. Most frequently, reductionist approaches are followed for deciphering the neuronal circuits functionally associated with cognitive processes. However, we argue that systemic studies of individual thought may still contribute to a useful and complementary description of the multimodal nature of perception, because they can take into account individual diversity while still identifying the common features of perceptual processes. We propose to address this question by looking at one possible task for recognition of a "signifying sound", as an example of conceptual grasping of a perceptual response. By adopting a mixed approach combining qualitative analyses of interviews based on introspection with quantitative statistical analyses carried out on the resulting categorization, this study describes a variety of mental strategies used by musicians to identify notes' pitch. Sixty-seven musicians (music students and professionals) were interviewed, revealing that musicians utilize intermediate steps during note identification by selecting or activating cognitive bricks that help construct and reach the correct decision. We named these elements "mental anchorpoints" (MA). Although the anchorpoints are not universal, and differ between individuals, they can be grouped into categories related to three main sensory modalities – auditory, visual and kinesthetic. Such categorization enabled us to characterize the mental representations (MR) that allow musicians to name notes in relationship to eleven basic typologies of anchorpoints. We propose a conceptual framework which summarizes the process of note identification in five steps, starting from sensory detection and ending with the verbalization of the note pitch, passing through the pivotal role of MAs and MRs. We found that musicians use multiple strategies and select individual combinations of MAs belonging to these three different sensory modalities, both in isolation and in combination. [ABSTRACT FROM AUTHOR]
Published: 2020
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28. Le difficile art de la publication scientifique et médicale.

Author: Teillaud, Jean-Luc
Published: 2023
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29. Progrès de la thérapie génique.

Author: Calvet, Charlotte, Lahlou, Ghizlene, and Safieddine, Saaid
Published: 2018
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30. Otoferlin acts as a Ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses.

Author: Michalski, Nicolas, Goutman, Juan D., Auclair, Sarah Marie, de Monvel, Jacques Boutet, Tertrais, Margot, Emptoz, Alice, Parrin, Alexandre, Nouaille, Sylvie, Guillon, Marc, Sachse, Martin, Ciric, Danica, Bahloul, Amel, Hardelin, Jean-Pierre, Sutton, Roger Bryan, Avan, Paul, Krishnakumar, Shyam S., Rothman, James E., Dulon, Didier, Safieddine, Saaid, and Petit, Christine
Published: 2017
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31. Conformational switch of harmonin, a submembrane scaffold protein of the hair cell mechanoelectrical transduction machinery.

Author: Bahloul, Amel, Pepermans, Elise, Raynal, Bertrand, Wolff, Nicolas, Cordier, Florence, England, Patrick, Nouaille, Sylvie, Baron, Bruno, El-Amraoui, Aziz, Hardelin, Jean-Pierre, Durand, Dominique, and Petit, Christine
Subjects: MEMBRANE proteins, SCAFFOLD proteins, HAIR cells, GENETIC transduction, CELLULAR signal transduction
Abstract: Mutations in the gene encoding harmonin, a multi- PDZ domain-containing submembrane protein, cause Usher syndrome type 1 (congenital deafness and balance disorder, and early-onset sight loss). The structure of the protein and biological activities of its three different classes of splice isoforms (a, b, and c) remain poorly understood. Combining biochemical and biophysical analyses, we show that harmonin-a1 can switch between open and closed conformations through intramolecular binding of its C-terminal PDZ-binding motif to its N-terminal supramodule NTD- PDZ1 and through a flexible PDZ2- PDZ3 linker. This conformational switch presumably extends to most harmonin isoforms, and it is expected to have an impact on the interaction with some binding partners, as shown here for cadherin-related 23, another component of the hair cell mechanoelectrical transduction machinery. [ABSTRACT FROM AUTHOR]
Published: 2017
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32. ANOS1: a unified nomenclature for Kallmann syndrome 1 gene (KAL1) and anosmin-1.

Author: de Castro, Fernando, Seal, Ruth, and Maggi, Roberto
Subjects: HYPOGONADISM, KLINEFELTER'S syndrome, KALLMANN syndrome, GENETIC disorders, CONGENITAL disorders
Abstract: It is accepted that confusion regarding the description of genetic variants occurs when researchers do not use standard nomenclature. The Human Genome Organization Gene Nomenclature Committee contacted a panel of consultants, all working on the KAL1 gene, to propose an update of the nomenclature of the gene, as there was a convention in the literature of using the 'KAL1' symbol, when referring to the gene, but using the name 'anosmin-1' when referring to the protein. The new name, ANOS1, reflects protein name and is more transferrable across species. [ABSTRACT FROM AUTHOR]
Published: 2017
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33. Defective signaling through plexin-A1 compromises the development of the peripheral olfactory system and neuroendocrine reproductive axis in mice.

Author: Marcos, Séverine, Monnier, Carine, Rovira, Xavier, Fouveaut, Corinne, Pitteloud, Nelly, Ango, Fabrice, Dodé, Catherine, and Hardelin, Jean-Pierre
Published: 2017
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34. Vers une thérapie génique de certaines surdités congénitales ?

Author: Hardelin, Jean-Pierre and Safieddine, Saaid
Published: 2019
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35. Diversity of the causal genes in hearing impaired Algerian individuals identified by whole exome sequencing.

Author: Ammar‐Khodja, Fatima, Bonnet, Crystel, Dahmani, Malika, Ouhab, Sofiane, Lefèvre, Gaelle M., Ibrahim, Hassina, Hardelin, Jean‐Pierre, Weil, Dominique, Louha, Malek, and Petit, Christine
Subjects: CONGENITAL disorders, MOLECULAR diagnosis, NUCLEOTIDE sequence, DEAFNESS, GENETIC mutation
Abstract: The genetic heterogeneity of congenital hearing disorders makes molecular diagnosis expensive and time-consuming using conventional techniques such as Sanger sequencing of DNA. In order to design an appropriate strategy of molecular diagnosis in the Algerian population, we explored the diversity of the involved mutations by studying 65 families affected by autosomal recessive forms of nonsyndromic hearing impairment (DFNB forms), which are the most prevalent early onset forms. We first carried out a systematic screening for mutations in GJB2 and the recurrent p.(Arg34*) mutation in TMC1, which were found in 31 (47.7%) families and 1 (1.5%) family, respectively. We then performed whole exome sequencing in nine of the remaining families, and identified the causative mutations in all the patients analyzed, either in the homozygous state (eight families) or in the compound heterozygous state (one family): (c.709C>T: p.(Arg237*)) and (c.2122C>T: p.(Arg708*)) in OTOF, (c.1334T>G: p.(Leu445Trp)) in SLC26A4, (c.764T>A: p.(Met255Lys)) in GIPC3, (c.518T>A: p.(Cys173Ser)) in LHFPL5, (c.5336T>C: p.(Leu1779Pro)) in MYO15A, (c.1807G>T: p.(Val603Phe)) in OTOA, (c.6080dup: p.(Asn2027Lys*9)) in PTPRQ, and (c.6017del: p.(Gly2006Alafs*13); c.7188_7189ins14: p.(Val2397Leufs*2)) in GPR98. Notably, 7 of these 10 mutations affecting 8 different genes had not been reported previously. These results highlight for the first time the genetic heterogeneity of the early onset forms of nonsyndromic deafness in Algerian families. [ABSTRACT FROM AUTHOR]
Published: 2015
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36. Reviewer acknowledgement 2015.

Author: Aymé, Ségolène
Subjects: PERIODICAL editors
Abstract: People whom the editors of the journal "Orphanet Journal of Rare Diseases" would like to thank for their contribution to the journal is presented which includes researcher Zohar Argov, Jean Bastin and Neil Basu.
Published: 2015
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37. Genetics of auditory mechano-electrical transduction.

Author: Michalski, Nicolas and Petit, Christine
Subjects: MECHANOTRANSDUCTION (Cytology), AUDITORY neurons, NEUROGENETICS, HAIR cells, MOLECULAR biology, COCHLEA
Abstract: The hair bundles of cochlear hair cells play a central role in the auditory mechano-electrical transduction (MET) process. The identification of MET components and of associated molecular complexes by biochemical approaches is impeded by the very small number of hair cells within the cochlea. In contrast, human and mouse genetics have proven to be particularly powerful. The study of inherited forms of deafness led to the discovery of several essential proteins of the MET machinery, which are currently used as entry points to decipher the associated molecular networks. Notably, MET relies not only on the MET machinery but also on several elements ensuring the proper sound-induced oscillation of the hair bundle or the ionic environment necessary to drive the MET current. Here, we review the most significant advances in the molecular bases of the MET process that emerged from the genetics of hearing. [ABSTRACT FROM AUTHOR]
Published: 2015
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38. Stratégies utilisées par les musiciens pour identifier la hauteur des notes : briques cognitives et représentations mentales

Author: Letailleur, Alain, Bisesi, Erica, Legrain, Pierre, Centre Georg Simmel (EHESS - UMR 8131), Perception et Mémoire / Perception and Memory, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Ce travail a été soutenu et partiellement financé par la SACEM, and Cette étude n'aurait pas été possible sans la précieuse contribution de tous les participants. Nous les remercions tous chaleureusement. Toute notre reconnaissance va à Heinz Wismann et Pierre-Marie Lledo pour leur intérêt et leur encouragement constants pendant le développement de ce projet. Nous remercions également Jean-Pierre Hardelin, Jean-Michel Hupé, Lydie Lane, Pierre-Marie Lledo, Antoine Nissant et Heinz Wismann pour leurs commentaires très utiles sur la version initiale du manuscrit. Nous sommes reconnaissants à tous les reviewers anonymes et à l’éditeur pour leurs remarques très pertinentes et leurs nombreuses suggestions d'amélioration de la version initiale de ce document.
Subjects: Phénoménologie, Mots-clés : Appui mental, Hauteur des notes, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Introspection, Représentation mentale, Perception musicale multimodale
Abstract: Traduction française de l’article paru dans « Frontiers in Psychology, auditory cognitive neurosciences » sous le titre original :Strategies used by musicians to identify notes’ pitch: Cognitive bricks and mental representationsFront. Psychol. 11:1480. doi: 10.3389/fpsyg.2020.01480; À ce jour, l'étude de la texture de la pensée et de ses mécanismes implicites est rarement abordée directement. Les approches systémiques basées sur des méthodologies introspectives ne sont actuellement plus à la mode et se trouvent souvent négligées ou ignorées. Le plus souvent, des approches réductionnistes sont réalisées pour déchiffrer les circuits neuronaux fonctionnellement associés aux processus cognitifs. Toutefois, nous soutenons que des études systémiques de la pensée individuelle peuvent encore contribuer à une description utile et complémentaire de la nature multimodale de la perception, car elles sont en mesure de prendre en compte la diversité individuelle tout en identifiant les caractéristiques communes des processus perceptifs. Nous proposons d'aborder cette question en examinant la tâche de reconnaissance d'un "son signifiant" comme exemple de saisie conceptuelle d'une réponse perceptive. En adoptant une approche mixte, combinant des analyses qualitatives d'entretiens basées sur l'introspection avec des analyses statistiques quantitatives réalisées sur la catégorisation qui en résulte, cette étude décrit une variété de stratégies mentales utilisées par les musiciens pour identifier la hauteur des notes. Soixante-sept musiciens (étudiants en musique et professionnels) ont été interrogés, révélant que les musiciens utilisent des étapes intermédiaires lors de l'identification des notes en sélectionnant ou en activant des briques cognitives qui aident à construire et à obtenir la bonne réponse. Nous avons nommé ces éléments "appuis mentaux". Bien que les appuis mentaux ne soient pas universels et diffèrent selon les individus, ils peuvent être regroupés en catégories liées à trois modalités sensorielles principales : auditive, visuelle et kinesthésique. Cette catégorisation nous a permis de caractériser les représentations mentales qui permettent aux musiciens de nommer des notes en fonction de onze typologies de base d'appuis mentaux. Nous proposons un cadre conceptuel qui résume le processus d'identification des notes en cinq étapes, partant de la détection sensorielle et se terminant par la verbalisation de la hauteur de la note, en passant par le rôle pivot des appuis mentaux et des représentations mentales. Nous avons constaté que les musiciens utilisent de multiples stratégies et sélectionnent des combinaisons individuelles d'appuis mentaux appartenant à ces trois différentes modalités sensorielles, à la fois isolément et en combinaison.
Published: 2020
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39. Strategies Used by Musicians to Identify Notes' Pitch: Cognitive Bricks and Mental Representations

Author: Pierre Legrain, Alain Letailleur, E. Bisesi, Centre Georg Simmel (EHESS - UMR 8131), Perception et Mémoire / Perception and Memory, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This work was supported and partly funded by SACEM, This study would not have been possible without the precious contributions by all the participants. We warmly thank all of them. A special gratitude is also due to Heinz Wismann and Pierre-Marie Lledo for their constant interest and encouragement during the development of the project. We also thank Jean-Pierre Hardelin, Jean-Michel Hupé, Lydie Lane, Pierre-Marie Lledo, Antoine Nissant, and Heinz Wismann for very useful comments on the initial version of the manuscript. We are grateful to all the referees and to the editor for very accurate remarks and useful suggestions for improvements., Centre Georg Simmel - Recherches franco-allemandes en sciences sociales, Centre de recherches interdisciplinaires sur l'Allemagne (CRIA), École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS)-École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: media_common.quotation_subject, lcsh:BF1-990, multimodal music perception, 050105 experimental psychology, 03 medical and health sciences, note pitch, 0302 clinical medicine, Stimulus modality, Perception, Psychology, 0501 psychology and cognitive sciences, General Psychology, media_common, Original Research, mental representation, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, introspection, 05 social sciences, Kinesthetic learning, Cognition, mental anchorpoint, lcsh:Psychology, Categorization, Conceptual framework, Mental representation, Introspection, phenomenology, 030217 neurology & neurosurgery, Cognitive psychology
Abstract: Une version traduite de cet article est disponible sur HAL sous le titre : Stratégies utilisées par les musiciens pour identifier la hauteur des notes : briques cognitives et représentations mentales. docid: pasteur-02901456; International audience; To this day, the study of the substratum of thought and its implied mechanisms is rarely directly addressed. Nowadays, systemic approaches based on introspective methodologies are no longer fashionable and are often overlooked or ignored. Most frequently, reductionist approaches are followed for deciphering the neuronal circuits functionally associated with cognitive processes. However, we argue that systemic studies of individual thought may still contribute to a useful and complementary description of the multimodal nature of perception, because they can take into account individual diversity while still identifying the common features of perceptual processes. We propose to address this question by looking at one possible task for recognition of a “signifying sound”, as an example of conceptual grasping of a perceptual response. By adopting a mixed approach combining qualitative analyses of interviews based on introspection with quantitative statistical analyses carried out on the resulting categorization, this study describes a variety of mental strategies used by musicians to identify notes’ pitch. Sixty-seven musicians (music students and professionals) were interviewed, revealing that musicians utilize intermediate steps during note identification by selecting or activating cognitive bricks that help construct and reach the correct decision. We named these elements “mental anchorpoints” (MA). Although the anchorpoints are not universal, and differ between individuals, they can be grouped into categories related to three main sensory modalities – auditory, visual and kinesthetic. Such categorization enabled us to characterize the mental representations (MR) that allow musicians to name notes in relationship to eleven basic typologies of anchorpoints. We propose a conceptual framework which summarizes the process of note identification in five steps, starting from sensory detection and ending with the verbalization of the note pitch, passing through the pivotal role of MAs and MRs. We found that musicians use multiple strategies and select individual combinations of MAs belonging to these three different sensory modalities, both in isolation and in combination.
Published: 2019
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40. Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome

Author: Omar Akil, Didier Dulon, Samantha Papal, Vincent Michel, Paul Avan, Alice Emptoz, Aziz El-Amraoui, Olinda Alegria-Prévot, Sedigheh Delmaghani, Pranav Patni, Lawrence R. Lustig, Christine Petit, Alain Aghaie, Abdelaziz Tlili, Elise Pepermans, Yohan Bouleau, Saaid Safieddine, Margot Tertrais, Matteo Cortese, Philippe F.Y. Vincent, Neurophysiologie de la Synapse Auditive, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU de Bordeaux Pellegrin [Bordeaux]-Neuroscience Institute, Génétique et Physiologie de l'Audition, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), ED 515 - Complexité du vivant, Université Pierre et Marie Curie - Paris 6 (UPMC), University of California [San Francisco] (UC San Francisco), University of California (UC), Columbia University [New York], Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre National de la Recherche Scientifique (CNRS), Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), SP and MC benefited from fellowships from the Ministry of National Education, Research and Technology of France, and PP from the European Union’s Horizon 2020 Marie Sklodowska-Curie grant 665807. This work was supported by European Research Council (ERC) advanced grant 'Hair bundle' (ERC-2011-AdG 294570), the European Union Seventh Framework Programme under grant agreement HEALTH-F2-2010-242013 (TREATRUSH), the French National Research Agency (ANR) as part of the second 'Investissements d’Avenir' programme (light4deaf, ANR-15-RHUS-0001), ANR-HearInNoise-(ANR-17-CE16-0017), LHW-Stiftung, FAUN Stiftung (Suchert Foundation), LABEX Life-senses (ANR-10-LABX-65), and a grant from the Fondation Pour l’Audition to DD (2015-APA Research Grant)., We thank Jean-Pierre Hardelin and Jacques Boutet de Monvel for critical reading of the manuscript., ANR-15-RHUS-0001,LIGHT4DEAF,ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER(2015), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), European Project: 294570,EC:FP7:ERC,ERC-2011-ADG_20110310,HAIRBUNDLE(2012), European Project: 242013,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,TREATRUSH(2010), Neuroscience Institute-Université de Bordeaux ( UB ) -CHU de Bordeaux Pellegrin [Bordeaux]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Collège de France ( CdF ) -Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Biologie du fruit et pathologie ( BFP ), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique ( INRA ) -Université Sciences et Technologies - Bordeaux 1, Laboratoire Biochimie et Biologie Moléculaire ( LBBM ), Université Hassan II, Neuro-Dol ( Neuro-Dol ), Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Neuro-Dol - Clermont Auvergne ( Neuro-Dol ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Clermont Auvergne ( UCA ) -Université Clermont Auvergne ( UCA ), Comité Français de la Semoulerie Industrielle ( CFSI ), Génétique et physiologie de l'audition, This work was supported by European Research Council (ERC) advanced grant 'Hair bundle' (ERC-2011-AdG 294570), the European Union Seventh Framework Programme under grant agreement HEALTH-F2-2010-242013 (TREATRUSH), the French National Research Agency (ANR) as part of the second 'Investissements d’Avenir' programme (light4deaf, ANR-15-RHUS-0001), ANR-HearInNoise-(ANR-17-CE16-0017), LHW-Stiftung, FAUN Stiftung (Suchert Foundation), LABEX Life-senses (ANR-10-LABX-65), and a grant from the Fondation Pour l’Audition to DD (2015-APA Research Grant)., ANR-15-RHUS-0001,LIGHT4DEAF,ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER ( 2015 ), ANR-17-CE16-0017,HearInNoise,Surdité d’apparition tardive et progressive: de la physiopathologie à la thérapie ( 2017 ), ANR-11-IDEX-0004-02/10-LABX-0065,LIFESENSES,DES SENS POUR TOUTE LA VIE ( 2011 ), European Project : 294570,EC:FP7:ERC,ERC-2011-ADG_20110310,HAIRBUNDLE ( 2012 ), European Project : 242013,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,TREATRUSH ( 2010 ), Neuroscience Institute-Université de Bordeaux (UB)-CHU de Bordeaux Pellegrin [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), University of California [San Francisco] (UCSF), University of California, Chaire Génétique et physiologie cellulaire, Oficjalska, Danuta, ECLAIRER LA SURDITÉ : UNE APPROCHE HOLISTIQUE DU SYNDROME D'USHER - - LIGHT4DEAF2015 - ANR-15-RHUS-0001 - RHUS - VALID, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, Assembling the puzzle of the operating auditory hair bundle - HAIRBUNDLE - - EC:FP7:ERC2012-12-01 - 2017-11-30 - 294570 - VALID, and Fighting blindness of Usher syndrome: diagnosis, pathogenesis and retinal treatment (TreatRetUsher) - TREATRUSH - - EC:FP7:HEALTH2010-02-01 - 2014-01-31 - 242013 - VALID
Subjects: 0301 basic medicine, Calcium Channels, L-Type, Usher syndrome, PDZ domain, Cell Cycle Proteins, AMPA receptor, Ribbon synapse, Biology, 03 medical and health sciences, Mice, 0302 clinical medicine, Gene therapy, Postsynaptic potential, Hair Cells, Auditory, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, otorhinolaryngologic diseases, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Receptors, AMPA, Mice, Knockout, Gene Transfer Techniques, Membrane Proteins, General Medicine, Genetic Therapy, Dependovirus, medicine.disease, Cell biology, Cytoskeletal Proteins, Disease Models, Animal, Calcium channels, 030104 developmental biology, medicine.anatomical_structure, Knockout mouse, Synapses, Synaptopathy, Human medicine, Hair cell, [ SCCO ] Cognitive science, Carrier Proteins, Usher Syndromes, 030217 neurology & neurosurgery, Research Article, Neuroscience
Abstract: Clarin-1, a tetraspan-like membrane protein defective in Usher syndrome type IIIA (USH3A), is essential for hair bundle morphogenesis in auditory hair cells. We report a new synaptic role for clarin-1 in mouse auditory hair cells elucidated by characterization of Clrn1 total (Clrn1(ex4-/-)) and postnatal hair cell-specific conditional (Clrn1(ex4fl/fl) Myo15-Cre(+/-)) knockout mice. Clrn1(ex4-/-) mice were profoundly deaf, whereas Clrn1(ex4fl/fl) Myo15-Cre(+/-) mice displayed progressive increases in hearing thresholds, with, initially, normal otoacoustic emissions and hair bundle morphology. Inner hair cell (IHC) patch-clamp recordings for the 2 mutant mice revealed defective exocytosis and a disorganization of synaptic F-actin and Ca(V)1.3 Ca2+ channels, indicative of a synaptopathy. Postsynaptic defects were also observed, with an abnormally broad distribution of AMPA receptors associated with a loss of afferent dendrites and defective electrically evoked auditory brainstem responses. Protein-protein interaction assays revealed interactions between clarin-1 and the synaptic Ca(V)1.3 Ca2+ channel complex via the Ca-V beta(2) auxiliary subunit and the PDZ domain-containing protein harmonin (defective in Usher syndrome type IC). Cochlear gene therapy in vivo, through adeno-associated virus-mediated Clrn1 transfer into hair cells, prevented the synaptic defects and durably improved hearing in Clrn1(ex4fl/fl) Myo15-Cre(+/-) mice. Our results identify clarin-1 as a key organizer of IHC ribbon synapses, and suggest new treatment possibilities for USH3A patients.
Published: 2018
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41. DNABarcodeCompatibility: an R-package for optimizing DNA-barcode combinations in multiplex sequencing experiments.

Author: Trébeau, Céline, Monvel, Jacques Boutet de, Tai, Fabienne Wong Jun, Petit, Christine, and Etournay, Raphaël
Subjects: WEB-based user interfaces, USER interfaces, SOURCE code, BAR codes, MATHEMATICAL combinations
Abstract: Summary Using adequate DNA barcodes is essential to unambiguously identify each DNA library within a multiplexed set of libraries sequenced using next-generation sequencers. We introduce DNABarcodeCompatibility, an R-package that allows one to design single or dual-barcoding multiplex experiments by imposing desired constraints on the barcodes (including sequencer chemistry, barcode pairwise minimal distance and nucleotide content), while optimizing barcode frequency usage, thereby allowing one to both facilitate the demultiplexing step and spare expensive library-preparation kits. The package comes with a user-friendly interface and a web app developed in Java and Shiny (https://dnabarcodecompatibility.pasteur.fr), respectively, with the aim to help bridge the expertise of core facilities with the experimental needs of non-experienced users. Availability and implementation DNABarcodeCompatibility can be easily extended to fulfil specific project needs. The source codes of the R-package and its user interfaces are publicly available along with documentation at [ https://github.com/comoto-pasteur-fr ] under the GPL-2 licence. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]
Published: 2019
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42. Interaction of protocadherin-15 with the scaffold protein whirlin supports its anchoring of hair-bundle lateral links in cochlear hair cells.

Author: Michel, Vincent, Pepermans, Elise, Boutet de Monvel, Jacques, England, Patrick, Nouaille, Sylvie, Aghaie, Alain, Delhommel, Florent, Wolff, Nicolas, Perfettini, Isabelle, Hardelin, Jean-Pierre, Petit, Christine, and Bahloul, Amel
Subjects: HAIR cells, CADHERINS, PROTEINS, CYTOSKELETON, MORPHOGENESIS
Abstract: The hair bundle of cochlear hair cells is the site of auditory mechanoelectrical transduction. It is formed by three rows of stiff microvilli-like protrusions of graduated heights, the short, middle-sized, and tall stereocilia. In developing and mature sensory hair cells, stereocilia are connected to each other by various types of fibrous links. Two unconventional cadherins, protocadherin-15 (PCDH15) and cadherin-23 (CDH23), form the tip-links, whose tension gates the hair cell mechanoelectrical transduction channels. These proteins also form transient lateral links connecting neighboring stereocilia during hair bundle morphogenesis. The proteins involved in anchoring these diverse links to the stereocilia dense actin cytoskeleton remain largely unknown. We show that the long isoform of whirlin (L-whirlin), a PDZ domain-containing submembrane scaffold protein, is present at the tips of the tall stereocilia in mature hair cells, together with PCDH15 isoforms CD1 and CD2; L-whirlin localization to the ankle-link region in developing hair bundles moreover depends on the presence of PCDH15-CD1 also localizing there. We further demonstrate that L-whirlin binds to PCDH15 and CDH23 with moderate-to-high affinities in vitro. From these results, we suggest that L-whirlin is part of the molecular complexes bridging PCDH15-, and possibly CDH23-containing lateral links to the cytoskeleton in immature and mature stereocilia. [ABSTRACT FROM AUTHOR]
Published: 2020
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43. Cranial Nerves: Anatomy, Function and Clinical Significance

Author: Thomas M. Yi and Thomas M. Yi
Subjects: Nerves, Cranial, Nerves, Cranial--Anatomy
Abstract: Cranial Nerves: Anatomy, Function and Clinical Significance opens with a summary of the current data on the clinical anatomy and developmental anomalies of the first cranial nerve, the olfactory nerve. Following this, the authors provide an overview of the second cranial nerve, the optic nerve, which is a vital component of the visual pathway. The seventh cranial nerve, the facial nerve, which contains the somatic motor and visceral motor, as well as special sensory and general sensory fibers is discussed. The 10th cranial nerve, the vagus nerve, is explored in closing, focusing on its motor functions responsible for the innervations of the outer ear canal, pharynx, larynx, heart, lung, gastrointestinal tract, stomach, pancreas and liver.
Published: 2021

44. Epstein's Inborn Errors of Development : The Molecular Basis of Clinical Disorders of Morphogenesis

Author: Robert P. Erickson MD, Anthony J. Wynshaw-Boris MD, PhD, Robert P. Erickson MD, and Anthony J. Wynshaw-Boris MD, PhD
Subjects: Genetic Diseases, Inborn--genetics, Congenital Abnormalities--genetics, Morphogenesis--genetics
Abstract: This third edition of Epstein's Inborn Errors of Development provides essays on pathways of development and thoughtful reviews of dysmorphic syndromes for which the causative gene has been identified. The authors of the chapters on each disorder have provided in depth analyses of the role of the gene in the relevant developmental pathway and the mechanism by which mutations in the gene cause the developmental pathology.
Published: 2016

45. The Cadherin Superfamily : Key Regulators of Animal Development and Physiology

Author: Shintaro T. Suzuki, Shinji Hirano, Shintaro T. Suzuki, and Shinji Hirano
Subjects: Cadherins
Abstract: This book presents an overview of the entire field of cadherin research and provides the current basic concept of cadherins. Cadherins have been widely accepted as key regulators of animal development and physiological functions, and it also has become clear that they play essential roles in various human diseases. With contributions by leading scientists, the book covers various aspects of the cadherin superfamily including the history of cadherin research, basic properties of classical cadherins as well as non-classical cadherins, cadherin-associated proteins, and the roles of cadherins in health and diseases. In addition, the book presents some contradictory results and important unanswered questions, and the authors propose their working hypotheses or future directions, to inspire future studies. This volume enables graduate students and young researchers to learn the basics and gain a comprehensive image of the cadherin superfamily, and experts in the field will easily find various topics of interest in relevant areas of study. Additionally, a list of cadherin-related diseases is included for quick reference to cadherins in human diseases.
Published: 2016

46. Amenorrhea

Author: Ezechi, Oliver Chukwujekwu and Ezechi, Oliver Chukwujekwu
Subjects: Amenorrhea
Abstract: As the knowledge required for efficient delivery of quality women's healthcare continues to grow, disease-specific textbooks are required to specifically address all aspects of a condition. A general textbook may not be able to address this need due to space constraints. This book is written to fill this gap as it relates to amenorrhoea, a common challenge for women within the reproductive age. The reader is offered a comprehensive knowledge of amenorrhoea, its burden, causes, presentation and management in one book. The book covers all aspect of amenorrhoea, which ordinarily is not covered by general textbooks of gynaecology. This compilation addresses various causes of amenorrhoea, from common causes such as hyperprolactinaemia to rare causes like Kallmann's syndrome and female athlete triad. The chapters are arranged in a logical and easy-to-follow style from general to specific issues making the book a daily guide as well as a reference text on amenorrhoea. The book's multi-author design is deliberate to ensure not only depth and breadth, but diversity as well. It also ensures that the experience and expertise of over twenty authors is brought to bear concerning the content. In addition, the authors utilise the available evidence moderated by their experience to produce a simple and straightforward guide for the practising gynaecologist, resident, general medical practitioner and others interested in providing quality reproductive health care to women in low, middle and high-income countries. Experienced gynaecologists and trainers will also find this book a very useful companion and guide.
Published: 2016

47. Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome

Author: Dulon, Didier, Papal, Samantha, Patni, Pranav, Cortese, Matteo, Vincent, Philippe F.Y., Tertrais, Margot, Emptoz, Alice, Tlili, Abdelaziz, Bouleau, Yohan, Michel, Vincent, Delmaghani, Sedigheh, Aghaie, Alain, Pepermans, Elise, Alegria-Prevot, Olinda, Akil, Omar, Lustig, Lawrence, Avan, Paul, Safieddine, Saaid, Petit, Christine, and Amraoui, Aziz El-
Subjects: Protein-protein interactions -- Analysis, Genetic transformation -- Research, Exocytosis -- Research, Usher's syndrome -- Models -- Genetic aspects -- Care and treatment -- Research, Health care industry
Abstract: Clarin-1, a tetraspan-like membrane protein defective in Usher syndrome type IIIA (USH3A), is essential for hair bundle morphogenesis in auditory hair cells. We report a new synaptic role for clarin-1 in mouse auditory hair cells elucidated by characterization of Clrn1 total ([Clrn1.sup.ex4-/-]) and postnatal hair cell- specific conditional ([Clrn1.sup.ex4fl/fl] [Myo15-Cre.sup.+/-) knockout mice. [Clrn1.sup.ex4-/-] mice were profoundly deaf, whereas [Clrn1.sup.ex4fl/fl] [Myo15-Cre.sup.+/-] mice displayed progressive increases in hearing thresholds, with, initially, normal otoacoustic emissions and hair bundle morphology. Inner hair cell (IHC) patch-clamp recordings for the 2 mutant mice revealed defective exocytosis and a disorganization of synaptic F-actin and [Ca.sub.V]1.3 [Ca.sup.2+] channels, indicative of a synaptopathy. Postsynaptic defects were also observed, with an abnormally broad distribution of AMPA receptors associated with a loss of afferent dendrites and defective electrically evoked auditory brainstem responses. Protein-protein interaction assays revealed interactions between clarin-1 and the synaptic [Ca.sub.V]1.3 [Ca.sup.2+] channel complex via the [Ca.sub.V][[beta].sub.2] auxiliary subunit and the PDZ domain-containing protein harmonin (defective in Usher syndrome type IC). Cochlear gene therapy in vivo, through adeno-associated virus-mediated Clrn1 transfer into hair cells, prevented the synaptic defects and durably improved hearing in [Clrn1.sup.ex4fl/fl] [Myo15-Cre.sup.+/-] mice. Our results identify clarin-1 as a key organizer of IHC ribbon synapses, and suggest new treatment possibilities for USH3A patients., Introduction Usher syndrome type IIIA (USH3A), characterized by progressive hearing loss and retinitis pigmentosa, is caused by mutations in CLRN1 encoding clarin-1 (refs. 1, 2, and Figure 1A). CLRN1 transcripts [...]
Published: 2018
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48. Studies from Pasteur Institute Describe New Findings in Science (Interaction of protocadherin-15 with the scaffold protein whirlin supports its anchoring of hair-bundle lateral links in cochlear hair cells)

Subjects: Health, Science and technology
Abstract: 2020 OCT 23 (NewsRx) -- By a News Reporter-Staff News Editor at Science Letter -- New research on science is the subject of a new report. According to news reporting [...]
Published: 2020

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