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18 results on '"Affections de la Myeline et des Canaux Ioniques Musculaires"'

1. The Treatabolome Database and Platform: enhancing Rare Diseases’ treatment visibility

Author

Hernandez-Ferrer, Carles, Matalonga, Leslie, Thompson, Rachel, Carmody, Leigh, Piscia, Davide, Macaya, Alfons, Lochmuller, Angela, Fontaine, Bertrand, Vicart, Sabine, Desaphy, Jean-François, Altamura, Concetta, Wahbi, Karim, de Sandre-Giovannoli, Annachiara, Vigouroux, Corinne, Zurek, Birte, Rheinard, Carola, Gómez-Andrés, David, Schon, Katherine, Over, Laura, Brüggemann, Norbert, Lohmann, Katja, Jennings, Matthew J, Synofzik, Matthis, Riess, Olaf, Yaou, Rabah Ben, Evangelista, Teresinha, Ratnaike, Thiloka, Bros-Facer, Virginie, Gumus, Gulcin, Horvath, Rita, Chinnery, Patrick, Laurie, Steven, Graessner, Holm, Robinson, Peter, Atalaia, Antonio, Lochmuller, Hanns, Bonne, Gisèle, Beltran, Sergi, Barcelona Institute of Science and Technology (BIST), Newcastle University [Newcastle], The Jackson Laboratory [Bar Harbor] (JAX), Universitat Autònoma de Barcelona (UAB), King‘s College London, Affections de la Myeline et des Canaux Ioniques Musculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Department of Pharmacy & Drug Sciences, Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Service de Cardiologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de ressources biologiques Tissus ADN Cellules [Hôpital de la Timone - APHM] (CRB TAC), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], University of Tübingen, Vall d'Hebron University Hospital [Barcelona], University of Cambridge [UK] (CAM), Department of Neurology, University of Luebeck, Institut de Myologie, and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Treatment delay, Rare diseases
Abstract

International audience

Published
2021

2. Expanding the phenotypic spectrum of Allan–Herndon–Dudley syndrome in patients with SLC 16A2 mutations

Author

Remerand, Ganaelle, Boespflug‐Tanguy, Odile, Tonduti, Davide, Touraine, Renaud, Rodriguez, Diana, Curie, Aurore, Perreton, Nathalie, Des Portes, Vincent, Sarret, Catherine, Afenjar, Alexandra, Burglen, Lydie, Castellotti, Barbara, Cuntz, Danielle, Desguerre, Isabelle, Doummar, Diane, Estienne, Margherita, Freri, Elena, Heron, Delphine, Moutard, Marie‐Laure, Novara, Francesca, Orcesi, Simona, Saletti, Veronica, Zibordi, Federica, Institut Pascal (IP), SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Clinique Chromosomique et Moléculaire, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Affections de la Myeline et des Canaux Ioniques Musculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Sciences cognitives Marc Jeannerod - Laboratoire sur le langage, le cerveau et la cognition (L2C2), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), CIC CHU Lyon (inserm), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire sur le langage, le cerveau et la cognition (L2C2), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service: neuropédiatrie pathologie du développement, Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cytogenetics, Fondation 'Neurological Institute C. Mondino ', Fondazione IRCCS Istituto Neurologico 'Carlo Besta', CHU Saint-Etienne-Hôpital Nord - Saint-Etienne, École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and SIGMA Clermont (SIGMA Clermont)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])

Subjects
030506 rehabilitation, Pediatrics, medicine.medical_specialty, Muscle Hypotonia, [SDV]Life Sciences [q-bio], Choreoathetosis, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Developmental Neuroscience, Intellectual disability, medicine, Kyphoscoliosis, ComputingMilieux_MISCELLANEOUS, Dystonia, Allan–Herndon–Dudley syndrome, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, medicine.disease, Hypotonia, 3. Good health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Pediatrics, Perinatology and Child Health, Neurology (clinical), medicine.symptom, 0305 other medical science, business, 030217 neurology & neurosurgery
Abstract

The aim of the study was to redefine the phenotype of Allan-Herndon-Dudley syndrome (AHDS), which is caused by mutations in the SLC16A2 gene that encodes the brain transporter of thyroid hormones. Clinical phenotypes, brain imaging, thyroid hormone profiles, and genetic data were compared to the existing literature. Twenty-four males aged 11 months to 29 years had a mutation in SLC16A2, including 12 novel mutations and five previously described mutations. Sixteen patients presented with profound developmental delay, three had severe intellectual disability with poor language and walking with an aid, four had moderate intellectual disability with language and walking abilities, and one had mild intellectual disability with hypotonia. Overall, eight had learned to walk, all had hypotonia, 17 had spasticity, 18 had dystonia, 12 had choreoathetosis, 19 had hypomyelination, and 10 had brain atrophy. Kyphoscoliosis (n=12), seizures (n=7), and pneumopathies (n=5) were the most severe complications. This study extends the phenotypic spectrum of AHDS to a mild intellectual disability with hypotonia. Developmental delay, hypotonia, hypomyelination, and thyroid hormone profile help to diagnose patients. Clinical course depends on initial severity, with stable acquisition after infancy; this may be adversely affected by neuro-orthopaedic, pulmonary, and epileptic complications. WHAT THIS PAPER ADDS: Mild intellectual disability is associated with SLC16A2 mutations. A thyroid hormone profile with a free T3 /T4 ratio higher than 0.75 can help diagnose patients. Patients with SLC16A2 mutations present a broad spectrum of neurological phenotypes that are also observed in other hypomyelinating disorders. Axial hypotonia is a consistent feature of Allan-Herndon-Dudley syndrome and leads to specific complications.

Published
2019

3. Systematic MRI in NF1 children under six years of age for the diagnosis of optic pathway gliomas. Study and outcome of a French cohort

Author

Pierre Castelnau, Sébastien Barbarot, Pierre Meyer, Marie-Pierre Lafforgue, Laurence Lion-François, Gaëlle Blanchard, Yves Chaix, Diana Rodriguez, Isabelle Kemlin, Maryline Carneiro, François Rivier, Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Affections de la Myeline et des Canaux Ioniques Musculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service de dermatologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Imagerie et cerveau

Subjects
Male, Optic Nerve Glioma, Pediatrics, medicine.medical_specialty, Neurofibromatosis 1, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Population, Neuroimaging, Asymptomatic, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Humans, Medicine, Mild visual impairment, Neurofibromatosis, Child, education, Children, Early Detection of Cancer, ComputingMilieux_MISCELLANEOUS, education.field_of_study, Chemotherapy, business.industry, Medical record, General Medicine, medicine.disease, Magnetic Resonance Imaging, 3. Good health, Optic gliomas, Child, Preschool, 030220 oncology & carcinogenesis, Pediatrics, Perinatology and Child Health, Cohort, Female, France, Neurology (clinical), medicine.symptom, Neurofibromatosis type 1 (NF1), business, 030217 neurology & neurosurgery, MRI
Abstract

Background/Purpose Optic pathway glioma (OPG) is the most common central nervous system tumor in children with neurofibromatosis type 1 (NF1), affecting 15–20% of patients. We reviewed the medical records of children systematically screened by ophthalmologic and MRI examinations to determine the influence of screening on the therapeutic management of children with OPG. Methods Data were collected on 306 newly diagnosed cases screened with systematic MRI from January 2001 to July 2007. In the OPG group, we distinguished the asymptomatic or symptomatic groups according to their initial status. Results Forty-five patients had confirmed OPG (14.7%). Thirty-six patients (80%) were asymptomatic and nine (20%) were symptomatic at the time of diagnosis with visual symptoms in six cases. The average age at OPG diagnosis was 3.4 years with six patients (13%) over six years old. Average follow-up was 7.7 years. Progression was observed in 16 cases (35%). Most patient conditions were managed conservatively (87%). Six children (13%) were treated with chemotherapy due to worsening visual function. All of these children had severe or mild visual impairment at the end of follow-up. Conclusion Our study does not support a clear benefit of systematic MRI screening in NF1 children under six years old. Systematic neuroimaging in our study did not influence therapeutic management. Although OPG diagnosis was made early, treatment with chemotherapy did not improve the final visual outcome. If MRI remains the best tool for the diagnosis of cerebral and spinal pathologies in the NF1 population, our current study questions the usefulness of systematic MRI screening for OPG diagnosis. Conversely, this study suggests that the indication of neuroimaging should be dictated by the results of annual clinical and ophthalmological assessments.

Published
2016

4. Mutations in GFPT1-related congenital myasthenic syndromes are associated with synaptic morphological defects and underlie a tubular aggregates myopathy with synaptopathy

Author

Bauché, Stéphanie, Vellieux, Geoffroy, Sternberg, Damien, Fontenille, Marie-Joséphine, Brochier, Guy, Lacène, Emmanuelle, Koenig, Jeanine, Fournier, Emmanuelle, Daniel, Hantaï, Eymard, Bruno, Chevessier, Frederic, Stojkovic, Tanya, Nicole, Sophie, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), 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 Sciences Cognitives et Sciences Affectives - UMR 9193 (SCALab), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Max-Planck-Institut für Medizinische Forschung, Max-Planck-Gesellschaft, Affections de la Myeline et des Canaux Ioniques Musculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and AFM-Théléton

Subjects
GFPT1, neuromuscular junction, CMS, [SDV]Life Sciences [q-bio]
Abstract

International audience; Mutations in GFPT1 (glutamine-fructose-6-phosphate transaminase 1), a gene encoding an enzyme involved in glycosylation of ubiquitous proteins, cause a limb-girdle congenital myasthenic syndrome (LG-CMS) with tubular aggregates (TAs) characterized predominantly by affection of the proximal skeletal muscles and presence of highly organized and remodeled sarcoplasmic tubules in patients’ muscle biopsies. GFPT1 is the first and rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP) involved in ubiquitous glycosylation processes (Senderek J. et al., 2011). Since 2011, a total of 52 patients with GFPT1 mutations have been clinically reported (Guergueltcheva V. et al., 2012; Senderek et al., 2011;Selcen D. et al., 2013; Huh S-Y. et al., 2012). In this study, we report the retrospective clinical description and the molecular investigations of 11 individuals from 9 unrelated families with LG-CMS linked to recessively-inherited mutations in GFPT1.Interestingly, GFPT1 is expressed in various tissues, including skeletal muscle and motor nerve, raising the intriguing question of why mutations in such a ubiquitous gene would specifically lead to synaptic and muscular disorganization.In this study, we report here the first long-term clinical follow-up of 11 French individuals suffering from LG-CMS with TAs due to GFPT1 mutations, of which 9 are new. Our retrospective clinical evaluation stresses an evolution toward a myopathic weakness that occurs concomitantly to ineffectiveness of usual CMS treatments. Analysis of neuromuscular biopsies from 3 unrelated individuals demonstrates that the maintenance of neuromuscular junctions (NMJs) is dramatically impaired with loss of post-synaptic junctional folds and evidence of denervation-reinnervation processes affecting the 3 main NMJ components. Moreover, molecular analyses of the human muscle biopsies confirm glycosylation defects of proteins with reduced O-glycosylation and show reduced sialylation of transmembrane proteins in extrajunctional area. Altogether, these results pave the way for understanding the etiology of this rare neuromuscular disorder that may be considered as a “tubular aggregates myopathy with synaptopathy”

Published
2017

5. Atypical clinical and radiological course of a patient with Canavan disease

Author

Catherine Sarret, Odile Boespflug-Tanguy, Diana Rodriguez, Institut Pascal (IP), SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Service de neurologie pédiatrique et maladies métaboliques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Affections de la Myeline et des Canaux Ioniques Musculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pascal - Clermont Auvergne (IP), Sigma CLERMONT (Sigma CLERMONT)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
0301 basic medicine, medicine.medical_specialty, Pathology, Neurology, Canavan Disease, Disease, Biology, Biochemistry, Amidohydrolases, White matter, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Basal ganglia, medicine, Humans, Child, ComputingMilieux_MISCELLANEOUS, Aspartic Acid, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, medicine.diagnostic_test, Metabolic disorder, Brain, Magnetic resonance imaging, medicine.disease, Magnetic Resonance Imaging, Canavan disease, 3. Good health, Aspartoacylase, 030104 developmental biology, medicine.anatomical_structure, Female, Neurology (clinical), 030217 neurology & neurosurgery
Abstract

Canavan disease (CD) is a rare metabolic disorder caused by aspartoacylase (ASPA) deficiency. It leads to severe neurological degeneration with spongiform brain degeneration. Accumulation of N-acetylaspartate (NAA) in brain and urine is specific to the disease and guides diagnosis. Magnetic resonance imaging (MRI) usually shows diffuse white matter abnormalities with involvement of the basal ganglia. Mild forms of the disease with a more favorable clinical course and radiological involvement of the basal ganglia without white matter abnormalities have also been reported. Here we report an atypical case of a girl aged nine years with CD. The disease started at the classical age of five months. Classical elevation of NAA in brain and urine was present and genetic analysis identified mutations in the ASPA gene. However, clinical evolution was milder than typical CD, with partial motor impairment and relatively well-preserved cognitive skills. MRI was also atypical with low white matter involvement and unusual topography and evolution of abnormalities in the basal ganglia.

Published
2016

6. Multiple Roles for Slits in the Control of Cell Migration in the Rostral Migratory Stream

Author

Anne Baron-Van Evercooren, Kim T. Nguyen-Ba-Charvet, Alain Chédotal, Nathalie Picard-Riera, Marc Tessier-Lavigne, Constantino Sotelo, Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Affections de la Myeline et des Canaux Ioniques Musculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Biology [Stanford], Stanford University, and INSERM, CEE QLK3-CT-1999-00894, French Ministry for Research (ACI number 5116), 'Association Pour la Recherche sur le Cancer', Fondation de France, Fondation de la Recherche Médicale (FRM).

Subjects
Rostral migratory stream, animal diseases, Development/Plasticity/Repair, Subventricular zone, Mice, Transgenic, Nerve Tissue Proteins, Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, Genes, Reporter, Interneurons, Lateral Ventricles, Neurosphere, SLIT1, medicine, SLIT2, Animals, Receptors, Immunologic, Cells, Cultured, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Chemotaxis, Stem Cells, General Neuroscience, Cell Differentiation, Cell migration, Olfactory Bulb, Slit, Olfactory bulb, Cell biology, medicine.anatomical_structure, nervous system, Choroid Plexus, Intercellular Signaling Peptides and Proteins, Septum of Brain, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuroscience, Cell Division, 030217 neurology & neurosurgery
Abstract

The subventricular zone (SVZ) contains undifferentiated cells, which proliferate and generate olfactory bulb (OB) interneurons. Throughout life, these cells leave the SVZ and migrate along the rostral migratory stream (RMS) to the OB where they differentiate.In vitro, the septum and the choroid plexus (CP) secrete repulsive factors that could orient the migration of OB precursors. Slit1 and Slit2, two known chemorepellents for developing axons, can mimic this effect. We show here that the Slit receptors Robo2 and Robo3/Rig-1 are expressed in the SVZ and the RMS and that Slit1 and Slit2 are still present in the adult septum. UsingSlit1/2-deficient mice, we found that Slit1 and Slit2 are responsible for both the septum and the CP repulsive activityin vitro. In adult mice lacking Slit1, small chains of SVZ-derived cells migrate caudally into the corpus callosum, supporting a role for Slits in orienting the migration of SVZ cells. Surprisingly, in adult mice, Slit1 was also expressed by type A and type C cells in the SVZ and RMS, suggesting that Slit1 could act cell autonomously. This hypothesis was tested using cultures of SVZ explants or isolated neurospheres fromSlit1-/- orSlit1+/- mice. In both types of cultures, the migration of SVZ cells was altered in the absence of Slit1. This suggests that the regulation of the migration of OB precursors by Slit proteins is complex and not limited to repulsion.

Published
2004

7. Peripheral nerve hyperexcitability with preterminal nerve and neuromuscular junction remodeling is a hallmark of Schwartz-Jampel syndrome

Author

Delphine Boërio, Michel Fardeau, Bertrand Fontaine, Véronique Bernard, Sophie Nicole, S. Bauche, Bruno Eymard, Jeanine Koenig, Claire-Sophie Davoine, Daniel Hantaï, Norma B. Romero, Emmanuel Fournier, Morgane Stum, Antoine Gueguen, Cécile Bureau, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), 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), CNRS, Laboratoire de Neurobiologie et Développement, Centre National de la Recherche Scientifique (CNRS), Affections de la Myeline et des Canaux Ioniques Musculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Physico-Chimie-Curie (PCC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Fondation Ophtalmologique Adolphe de Rothschild [Paris], 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), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC), Centre de référence des maladies rares neuromusculaires, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), 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 Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Receptor, ErbB-3, Schwartz–Jampel syndrome, [SDV]Life Sciences [q-bio], Neuromuscular transmission, Neural Conduction, Neuromuscular Junction, Perlecan, Biology, Osteochondrodysplasias, Neuromuscular junction, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Neurofilament Proteins, medicine, Humans, Receptors, Cholinergic, Peripheral Nerves, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Denervation, 0303 health sciences, Electromyography, Calcium-Binding Proteins, S100 Proteins, Electromyoneurography, Receptor Protein-Tyrosine Kinases, Myelin Basic Protein, Anatomy, medicine.disease, Acetylcholinesterase, medicine.anatomical_structure, Neurology, chemistry, Pediatrics, Perinatology and Child Health, biology.protein, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), 030217 neurology & neurosurgery, Reinnervation
Abstract

Schwartz-Jampel syndrome (SJS) is a recessive disorder with muscle hyperactivity that results from hypomorphic mutations in the perlecan gene, a basement membrane proteoglycan. Analyses done on a mouse model have suggested that SJS is a congenital form of distal peripheral nerve hyperexcitability resulting from synaptic acetylcholinesterase deficiency, nerve terminal instability with preterminal amyelination, and subtle peripheral nerve changes. We investigated one adult patient with SJS to study this statement in humans. Perlecan deficiency due to hypomorphic mutations was observed in the patient biological samples. Electroneuromyography showed normal nerve conduction, neuromuscular transmission, and compound nerve action potentials while multiple measures of peripheral nerve excitability along the nerve trunk did not detect changes. Needle electromyography detected complex repetitive discharges without any evidence for neuromuscular transmission failure. The study of muscle biopsies containing neuromuscular junctions showed well-formed post-synaptic element, synaptic acetylcholinesterase deficiency, denervation of synaptic gutters with reinnervation by terminal sprouting, and long nonmyelinated preterminal nerve segments. These data support the notion of peripheral nerve hyperexcitability in SJS, which would originate distally from synergistic actions of peripheral nerve and neuromuscular junction changes as a result of perlecan deficiency.

Published
2013

8. A mouse model of schwartz-jampel syndrome reveals myelinating schwann cell dysfunction with persistent axonal depolarization in vitro and distal peripheral nerve hyperexcitability when perlecan is lacking

Author

Maria Laura Feltri, Jérôme Devaux, Frédérique René, Claire-Sophie Davoine, Sophie Nicole, Andoni Echaniz-Laguna, Marie Bangratz, Desirée Zambroni, Delphine Boerio, Nadège Sarrazin, Bertrand Fontaine, Evelyne Benoit, Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Neurologie, Hôpital Civil de Strasbourg, Affections de la Myeline et des Canaux Ioniques Musculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Active Perception Lab - Universiteit Antwerpen (APL), Universiteit Antwerpen = University of Antwerpen [Antwerpen], Neuropathology Unit, San Raffaele Scientific Institute-INSPE-Institute for Experimental Neurology, Neurobiologie et Développement (N&eD), Centre National de la Recherche Scientifique (CNRS), Institut de Neurobiologie Alfred Fessard (INAF), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universiteit Antwerpen, Fédération des Maladies du Système Nerveux, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Aging, Neuromyotonia, Schwartz–Jampel syndrome, Neuromuscular Junction, Action Potentials, Schwann cell, Perlecan, Biology, Osteochondrodysplasias, Basement Membrane, Article, Neuromuscular junction, Pathology and Forensic Medicine, Mice, 03 medical and health sciences, 0302 clinical medicine, Ranvier's Nodes, medicine, Animals, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Myelin Sheath, 030304 developmental biology, Denervation, Basement membrane, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, Depolarization, medicine.disease, Sciatic Nerve, Axons, Electric Stimulation, Mice, Mutant Strains, Cell biology, Disease Models, Animal, Microscopy, Electron, medicine.anatomical_structure, Mutation, Immunology, biology.protein, Schwann Cells, Kv1.1 Potassium Channel, Heparan Sulfate Proteoglycans, 030217 neurology & neurosurgery, Demyelinating Diseases
Abstract

International audience; Congenital peripheral nerve hyperexcitability (PNH) is usually associated with impaired function of voltage-gated K(+) channels (VGKCs) in neuromyotonia and demyelination in peripheral neuropathies. Schwartz-Jampel syndrome (SJS) is a form of PNH that is due to hypomorphic mutations of perlecan, the major proteoglycan of basement membranes. Schwann cell basement membrane and its cell receptors are critical for the myelination and organization of the nodes of Ranvier. We therefore studied a mouse model of SJS to determine whether a role for perlecan in these functions could account for PNH when perlecan is lacking. We revealed a role for perlecan in the longitudinal elongation and organization of myelinating Schwann cells because perlecan-deficient mice had shorter internodes, more numerous Schmidt-Lanterman incisures, and increased amounts of internodal fast VGKCs. Perlecan-deficient mice did not display demyelination events along the nerve trunk but developed dysmyelination of the preterminal segment associated with denervation processes at the neuromuscular junction. Investigating the excitability properties of the peripheral nerve suggested a persistent axonal depolarization during nerve firing in vitro, most likely due to defective K(+) homeostasis, and excluded the nerve trunk as the original site for PNH. Altogether, our data shed light on perlecan function by revealing critical roles in Schwann cell physiology and suggest that PNH in SJS originates distally from synergistic actions of peripheral nerve and neuromuscular junction changes.

Published
2012

9. Nouvel éclairage sur les hypoplasies pontocérébelleuses : apports des nouveaux gènes dans l'arbre décisionnel de diagnostic

Author

Burglen, Lydie, Moutard, Marie-Laure, Chantot-Bastaraud, Sandra, Joriot, Sylvie, Des Portes, Vincent, Afenjar, Alexandra, Garel, Catherine, Legall, Anne, Berthomé, Pascaline, Billette de Villemeur, T, Gelot, Antoinette, Rodriguez, Diana, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de neuropédiatrie, GHU Ouest, Service de Neuro-pédiatrie[Lille], Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire sur le langage, le cerveau et la cognition (L2C2), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U901), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Affections de la Myeline et des Canaux Ioniques Musculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Service de génétique et embryologie médicales [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), and Berger, Patrice

Subjects
[SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience
Published
2012

10. Etude clinique et génétique chez 80 patients atteints de syndrome de Joubert

Author

Burglen, Lydie, Afenjar, Alexandra, Garel, Catherine, Des Portes, Vincent, Moutard, Marie-Laure, Doummar, Diane, Rivier, Francois, Roubertie, Agathe, Philip, Nicole, Toutain, Annick, Ansallem, Daniel, Holder, Muriel, Boute, Odile, Odent, Sylvie, Thauvin, Christel, Rodriguez, Diana, Berger, Patrice, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique Médicale et Génomique Fonctionnelle (GMGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Service de génétique et embryologie médicales [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), Laboratoire sur le langage, le cerveau et la cognition (L2C2), École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Service de neuropédiatrie, GHU Ouest, Pediatric Neurology, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Service d'explorations fonctionnelles respiratoires [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Affections de la Myeline et des Canaux Ioniques Musculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier (INM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)

Subjects
[SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience
Published
2012

11. NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype

Author

Dominique Vidaud, Michel Vidaud, Jean Soulier, Marc Sanson, Eric Pasmant, Marie-José Hamel, Meena Upadhyaya, Sébastien Barbarot, Hélène Dollfus, Salah Ferkal, Gillian Spurlock, Béatrice Parfait, Anne Dieux-Coeslier, Bertrand Isidor, Ingrid Laurendeau, Audrey Sabbagh, Elisa Grillo, Diana Rodriguez, Ivan Bièche, Ludovic Martin, Didier Lacombe, Pierre Wolkenstein, Laurent Pasquier, B. Leheup, Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux ( Inserm U745 ), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Medical Genetics, Institute of Medical Genetics, Service de Biochimie et Génétique Moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Hôpital Beaujon, Department of Dermatology, Université d'Angers ( UA ), Service de Dermatologie, Hôtel Dieu, CHU de Nantes, Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Affections de la Myeline et des Canaux Ioniques Musculaires, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Pellegrin Hospital, Laboratoire de Génétique Médicale EA 3949, Faculté de Médecine de Strasbourg, Université de Strasbourg, Génétique et Développement, Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR97-Centre National de la Recherche Scientifique ( CNRS ), Service de Génétique Médicale, CIC - CHU Henri Mondor, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), 3UMR728 INSERM Unité d'immuno-hématologie (UIH) and laboratoire d'hématologie, Hôpital St-Louis, AP-HP, Département de neurologie 2 - Mazarin, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Center for Clinical Genetics, Hôpital Jeanne de Flandre [Lille], Service de dermatologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Cardiff University, Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux (Inserm U745), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université d'Angers (UA), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR97-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), UPMC - Département de neurologie 2 - Mazarin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-IFR97-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Beaujon-Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, Neurofibromatosis 1, Genotype, [SDV]Life Sciences [q-bio], Biology, medicine.disease_cause, Contiguous gene syndrome, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, Genetic Predisposition to Disease, Neurofibromatosis, 10. No inequality, neoplasms, Genetic Association Studies, Genetics (clinical), Sequence Deletion, 030304 developmental biology, Comparative Genomic Hybridization, 0303 health sciences, Mutation, Neurofibromin 1, [ SDV ] Life Sciences [q-bio], Gene Expression Profiling, Breakpoint, Life Sciences, Middle Aged, medicine.disease, Phenotype, eye diseases, nervous system diseases, Gene expression profiling, Regression Analysis, Female, 030217 neurology & neurosurgery, Comparative genomic hybridization
Abstract

International audience; In 5-10% of patients, neurofibromatosis type 1 (NF1) results from microdeletions that encompass the entire NF1 gene and a variable number of flanking genes. Two recurrent microdeletion types are found in most cases, with microdeletion breakpoints located in paralogous regions flanking NF1 (proximal NF1-REP-a and distal NF1-REP–c for the 1.4 Mb type-1 microdeletion, and SUZ12 and SUZ12P for the 1.2 Mb type-2 microdeletion). A more severe phenotype is usually associated with NF1 microdeletion patients than in those with intragenic mutations. We characterized NF1 microdeletions in 70 unrelated NF1 microdeleted patients using a high-resolution NF1 custom array comparative genomic hybridization (CGH). Genotype-phenotype correlations were studied in 58 of these microdeletion patients and compared to 389 patients with intragenic truncating NF1 mutations and phenotyped in the same standardized way. Our results confirmed in an unbiased manner the existence of a contiguous gene syndrome with a significantly higher incidence of learning disabilities and facial dysmorphism in microdeleted patients compared to patients with intragenic NF1 mutations. Microdeleted NF1 patients also showed a trend toward significance for childhood overgrowth. High-resolution array-CGH identified a new recurrent ~1.0 Mb microdeletion type, designated as type-3, with breakpoints in the paralogous regions middle NF1-REP-b and distal NF1-REP–c.

Published
2010

12. Gender and sex hormones in multiple sclerosis pathology and therapy

Author

Arnaud Nicot, Affections de la Myeline et des Canaux Ioniques Musculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Nicot, Arnaud

Subjects
Central Nervous System, Male, Pathology, medicine.medical_specialty, Multiple Sclerosis, [SDV.IMM] Life Sciences [q-bio]/Immunology, Experimental Allergic Encephalomyelitis, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Disease, TMEV, Review, Biology, Neuroprotection, Article, Th1, 03 medical and health sciences, Th2, 0302 clinical medicine, Immune system, Neuroinflammation, Autoimmune disease, medicine, Humans, Testosterone, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Gonadal Steroid Hormones, Progesterone, 030304 developmental biology, 0303 health sciences, Estradiol, Estriol, EAE, Multiple sclerosis, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.disease, 3. Good health, Treg, Sex steroid, Immune System, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030217 neurology & neurosurgery, Dendritic cell, Hormone
Abstract

International audience; Several lines of evidence indicate that gender affects the susceptibility and course of multiple sclerosis (MS) with a higher disease prevalence and overall better prognosis in women than men. This sex dimorphism may be explained by sex chromosome effects and effects of sex steroid hormones on the immune system, blood brain barrier or parenchymal central nervous system (CNS) cells. The well known improvement in disease during late pregnancy has also been linked to hormonal changes and has stimulated recent clinical studies to determine the efficacy of and tolerance to sex steroid therapeutic approaches. Both clinical and experimental studies indicate that sex steroid supplementation may be beneficial for MS. This could be related to anti-inflammatory actions on the immune system or CNS and to direct neuroprotective properties. Here, clinical and experimental data are reviewed with respect to the effects of sex hormones or gender in the pathology or therapy of MS or its rodent disease models. The different cellular targets as well as some molecular mechanisms likely involved are discussed.

Published
2009

13. Evidence of a dosage effect and a physiological endplate acetylcholinesterase deficiency in the first mouse models mimicking Schwartz-Jampel syndrome neuromyotonia

Author

Morgane Stum, Arnaud Ferry, Frédédrique Rene, Christophe Marcel, Andoni Echaniz-Laguna, Véronique Bernard, Claire-Sophie Davoine, Bertrand Fontaine, Eric Krejci, Sophie Nicole, Alban Vignaud, Marie Bangratz, Emmanuelle Girard, Jordi Molgó, Marc Herbin, Affections de la Myeline et des Canaux Ioniques Musculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de neurobiologie cellulaire et moléculaire (NBCM), Centre National de la Recherche Scientifique (CNRS), Institut de Neurobiologie Alfred Fessard (INAF), Biologie des Jonctions Neuromusculaires Normales et Pathologiques (U686), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Mécanismes adaptatifs : des organismes aux communautés (MAOAC), Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Groupe Myologie, Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de signalisation moléculaire et neurodégénerescence, Université Louis Pasteur - Strasbourg I-IFR37-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Neurologie, Hôpital Civil de Strasbourg, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Fédération des Maladies du Système Nerveux, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Muséum national d'Histoire naturelle (MNHN)-Collège de France (CdF)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Laboratoire de neurobiologie cellulaire et moléculaire ( NBCM ), Centre National de la Recherche Scientifique ( CNRS ), Institut de Neurobiologie Alfred Fessard ( INAF ), Biologie des Jonctions Neuromusculaires Normales et Pathologiques ( U686 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Mécanismes adaptatifs : des organismes aux communautés ( MAOAC ), Muséum National d'Histoire Naturelle ( MNHN ) -Collège de France ( CdF ) -Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Association française contre les myopathies ( AFM-Téléthon ) -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 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Association française contre les myopathies ( AFM-Téléthon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Louis Pasteur - Strasbourg I-IFR37-Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP]

Subjects
Male, Neuromyotonia, MESH: Mice, Mutant Strains, MESH: Muscle Contraction, Gene Dosage, medicine.disease_cause, MESH: Gene Dosage, MESH: Motor Endplate, chemistry.chemical_compound, Mice, 0302 clinical medicine, Missense mutation, MESH : Female, MESH : Gene Dosage, MESH: Animals, Genetics (clinical), 0303 health sciences, Mutation, biology, General Medicine, Acetylcholinesterase, MESH : Mice, Transgenic, MESH : Phenotype, medicine.anatomical_structure, Phenotype, MESH : Electromyography, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH : Heparan Sulfate Proteoglycans, Muscle Contraction, medicine.medical_specialty, MESH : Isaacs Syndrome, MESH: Mice, Transgenic, MESH : Male, Schwartz–Jampel syndrome, Mutation, Missense, Mice, Transgenic, MESH : Mice, Inbred C57BL, Perlecan, Osteochondrodysplasias, MESH: Phenotype, Motor Endplate, Neuromuscular junction, MESH : Acetylcholinesterase, MESH: Electromyography, 03 medical and health sciences, In vivo, MESH: Mice, Inbred C57BL, Internal medicine, MESH : Mice, Genetics, medicine, Animals, Humans, MESH: Isaacs Syndrome, Molecular Biology, MESH: Mice, Alleles, 030304 developmental biology, MESH : Osteochondrodysplasias, MESH: Mutation, Missense, MESH: Humans, Electromyography, MESH: Alleles, MESH : Humans, MESH : Motor Endplate, MESH: Acetylcholinesterase, medicine.disease, MESH: Osteochondrodysplasias, MESH : Disease Models, Animal, Mice, Mutant Strains, MESH: Male, MESH : Mice, Mutant Strains, Mice, Inbred C57BL, Disease Models, Animal, stomatognathic diseases, Endocrinology, chemistry, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], biology.protein, MESH: Heparan Sulfate Proteoglycans, MESH : Muscle Contraction, MESH : Animals, Isaacs Syndrome, MESH: Disease Models, Animal, MESH : Alleles, MESH: Female, MESH : Mutation, Missense, 030217 neurology & neurosurgery, Heparan Sulfate Proteoglycans
Abstract

International audience; Schwartz-Jampel syndrome (SJS) is a recessive neuromyotonia with chondrodysplasia. It results from hypomorphic mutations of the gene encoding perlecan, leading to a decrease in the levels of this heparan sulphate proteoglycan in basement membranes (BMs). It has been suggested that SJS neuromyotonia may result from endplate acetylcholinesterase (AChE) deficiency, but this hypothesis has never been investigated in vivo due to the lack of an animal model for neuromyotonia. We used homologous recombination to generate a knock-in mouse strain with one missense substitution, corresponding to a human familial SJS mutation (p.C1532Y), in the perlecan gene. We derived two lines, one with the p.C1532Y substitution alone and one with p.C1532Y and the selectable marker Neo, to down-regulate perlecan gene activity and to test for a dosage effect of perlecan in mammals. These two lines mimicked SJS neuromyotonia with spontaneous activity on electromyogramm (EMG). An inverse correlation between disease severity and perlecan secretion in the BMs was observed at the macroscopic and microscopic levels, consistent with a dosage effect. Endplate AChE levels were low in both lines, due to synaptic perlecan deficiency rather than major myofibre or neuromuscular junction disorganization. Studies of muscle contractile properties showed muscle fatigability at low frequencies of nerve stimulation and suggested that partial endplate AChE deficiency might contribute to SJS muscle stiffness by potentiating muscle force. However, physiological endplate AChE deficiency was not associated with spontaneous activity at rest on EMG in the diaphragm, suggesting that additional changes are required to generate such activity characteristic of SJS.

Published
2008

14. Vers la compréhension des mécanismes moléculaires et physiopathologiques à l'origine de l'hyperactivité neuromusculaire dans le syndrome de Schwartz-Jampel

Author

Stum, Morgane, Affections de la Myeline et des Canaux Ioniques Musculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris VI, Anne BARON-VAN-EVERCOOREN, and Bupmc, Theses

Subjects
data unavailable, Acétylcholinestérase, Jonction neuromusculaire, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, Raideur musculaire, Mutation hypomorphe, Modèle murin knock-in, Perlecan, Syndrome de Schwartz-Jampel, Hyperactivité
Abstract

We have demonstrated by RT-PCR, immunohistochemistry and ELISA that BMP-7 and its receptors are present in histologically normal human crypts, in aberrant crypt foci in sigmoiditis, in human colorectal tumors and in several colorectal cancer cell lines. We have also demonstrated that BMP-7 is a scatter and invasion factor. This invasive capacity of BMP-7 is independent of SMAD4 and src activity, but is associated to the cyclic activation of RhoGTPases (Rac1 and RhoA), to FAK activation (tyr925 phosphorylation associated with angiogenesis and invasion) and to MAPK/SAPK activation (JNK and ERK1/2).Taken together my PhD work strongly suggests that BMP-7 acts as dissemination and a proinvasive factor via an autocrine and paracrine mechanism. This cytokine has divergent roles on human colon cancer progression. A beneficial role, by opposing itself to inflammation and a pejorative role by helping cancer progression on the latest stages associated to invasive capacity and to adenoma-carcinoma transition Schwartz-Jampel syndrome (SJS) is an autosomal recessive human disease, characterized by muscle stiffness and chondrodysplasia and caused by mutations in the perlecan gene. During my PhD, we identified 22 new SJS mutations. Molecular analyzes (mRNA and protein) showed an hypomorph effect of these mutations, allowing the production of a residual amount of functional perlecan. In order to understand the pathophysiological mechanism leading to SJS, we generated a mouse model by inserting the SJS missense p.C1532Y mutation. Homozygous mutants are viable and fertile but show locomotor defects and neuromuscular hyperactivity. Cellular defects in skeletal muscles are suggestive of denervation-reinnervation processes. Neuromuscular junctions are remodelled with a lack of the typical pretzel-like shape, acetylcholinesterase (AChE) deficiency and partial denervation. Electrophysiological analyzes reveal functional consequences of AChE deficiency but not sufficient to lead to synaptic hyperactivity and an additional effect of presynaptic abnormalities is thus suggested., Le syndrome de Schwartz-Jampel (SJS) est une pathologie autosomique récessive rare car seulement plus de 100 cas ont été décrits dans la littérature. Elle est caractérisée par une raideur musculaire permanente et généralisée associée à une chondrodystrophie. Elle est due à des mutations perte de fonction dans le gène HSPG2 codant pour le perlecan, un héparane sulfate protéoglycane ubiquitaire présent dans les membranes basales et les matrices extracellulaires. Une autre pathologie, la dysplasie dissegmentaire de type Silvermann-Handmaker (DDSH) est due à des mutations perte de fonction dans ce gène, et est caractérisée par une chondrodysplasie très sévère menant à la mort du patient dès les premiers jours de vie. Dans une première partie de mon introduction, je décrirai les signes cliniques de ces deux pathologies et les mutations du gène HSPG2 actuellement connues pour chacune. Le perlecan est une des plus grandes protéines connues. Avec une séquence protéique de plus de 4300 acides aminés et un poids moléculaire de plus de 450kDa, il subit des modifications post-traductionnelles et peut alors atteindre un poids moléculaire de 800kDa. Cette protéine immense assure de multiples interactions et fonctions dans les membranes basales dans lesquelles elle est ubiquitairement présente. Afin de mieux comprendre quel rôle cette protéine peut jouer dans la détermination du phénotype dans le SJS, je détaillerai dans une seconde partie les différentes molécules avec lesquelles le perlecan interagit et les fonctions qu'il assume dans les deux principaux tissus d'intérêt de la pathologie : le cartilage et le muscle. Enfin, je décrirai le phénotype de mutants d'orthologues de gène HSPG2 dans les trois organismes modèles que sont la drosophile, le nématode et la souris. Au cours de ma thèse, je me suis plus particulièrement intéressée au phénotype neuromusculaire du SJS. Pour une meilleure compréhension de mes travaux, je rappellerai dans une troisième et dernière partie de mon introduction, la structure, le développement et le fonctionnement de la jonction neuromusculaire, ainsi que les pathologies humaines congénitales associées.

Published
2007

15. Silencing of the Charcot-Marie-Tooth associated MTMR2 gene decreases proliferation and enhances cell death in primary cultures of Schwann cells

Author

Anne Baron-Van Evercooren, Bernard Brugg, Corinne Bachelin, Nicole Ravisé, Jocelyn Laporte, Christel Depienne, Merle Ruberg, Alexandre Chojnowski, Eric LeGuern, Neurologie et thérapeutique expérimentale, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Affections de la Myeline et des Canaux Ioniques Musculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Département d'Astrophysique, de physique des Particules, de physique Nucléaire et de l'Instrumentation Associée (DAPNIA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), This work was supported by the Association Francaise contre les Myopathies (AFM), by Association de Recherche sur les Maladies Génétiques Neurologiques et Psychiatriques (ADRMGNP) and INSERM. A.C., N.R., A. B.-V. and E.L. are members of the 'GIS-Orphan' diseases research network on autosomal recessive forms of CMT. A.C. was supported by AFM., Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Schwann, Myotubularin, "Apoptosis", Proliferation, Apoptosis, Culture Media, Serum-Free, 0302 clinical medicine, RNA interference, Charcot-Marie-Tooth Disease, Cells, Cultured, Myelin Sheath, "Schwann", 0303 health sciences, Charcot–Marie–Tooth, Cell Death, Gene Expression Regulation, Developmental, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Protein Tyrosine Phosphatases, Non-Receptor, Cell biology, medicine.anatomical_structure, Neurology, Peripheral nervous system, Caspases, RNA Interference, Programmed cell death, "RNAi", Down-Regulation, Biology, lcsh:RC321-571, "Charcot–Marie–Tooth", 03 medical and health sciences, "Proliferation", medicine, Gene silencing, Animals, Gene Silencing, Peripheral Nerves, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Gene, Loss function, 030304 developmental biology, Cell Proliferation, Gene Expression Profiling, ACM, Rats, MTMR2, Animals, Newborn, nervous system, RNAi, Immunology, Schwann Cells, "MTMR2", Protein Tyrosine Phosphatases, 030217 neurology & neurosurgery
Abstract

Loss of function of the myotubularin (MTM)-related protein 2 (MTMR2) in Schwann cells causes Charcot–Marie–Tooth disease type 4B1, a severe demyelinating neuropathy, but the consequences of MTMR2 disruption in Schwann cells are unknown. We established the expression profile of MTMR2 by real-time RT-PCR during rat myelination and showed it to be preferentially expressed at the onset of the myelination period. We developed a model in which MTMR2 loss of function was reproduced in primary cultures of Schwann cells by RNA interference. We found that depletion of MTMR2 in Schwann cells decreased their rate of proliferation. Furthermore, when cultivated in serum-free medium, MTMR2 depletion increased the number of Schwann cells that died by a caspase-dependent process. These results support the hypothesis that loss of MTMR2 in patients, by decreasing Schwann cells proliferation and survival, may impair the first stages of myelination of the peripheral nervous system.

Published
2007

16. Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum

Author

Hamid Azzedine, Alessandro Filla, Merle Ruberg, Paula Coutinho, Filippo M. Santorelli, Enrico Bertini, Vítor Tedim Cruz, Elodie Martin, N. Elleuch, D. Grid, Jacques Chomilier, Alessandra Tessa, Naima Bouslam, Perrine Charles, Alexandra Durr, Bertrand Fontaine, Eric LeGuern, Paola S. Denora, Christian Confavreux, Giovanni Stevanin, Anne Marie Ouvrard-Hernandez, Alexis Brice, Meriem Tazir, José Leal Loureiro, Alexander Lossos, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unit of Molecular Medicine, IRCCS, UnIGENe, Universidade do Porto, Institut de minéralogie et de physique des milieux condensés (IMPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Département de neurologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Department of Neurology, Hadassah Hebrew University Medical Center [Jerusalem], Departamento de Neurologia, Hospital S. Sebastiao, Department of neurology, Hopital Habib Bourguiba - Habib Bourguiba Hospital [Sfax], Hopital Neurologique, Ministère de la santé, Service de Neurologie A-Hopital Neurologique Pierre Wertheimer, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Généthon, Service de Neurologie, Hopital Mustapha, Affections de la Myeline et des Canaux Ioniques Musculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Neurological Sciences, Università degli studi di Napoli Federico II, ANR-05-MRAR-0001,Cav3pathies,Approches physiopathologique et moléculaire de la signalisation calcique dans les caveolinopathies musculaires(2005), Université Mohammed V, Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital neurologique, Hospices Civils de Lyon (HCL), Neurologie Expérimentale et Thérapeutique, IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Mustapha, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), 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), Department of Computer Science and Engineering, New York University [New York] (NYU), NYU System (NYU)-NYU System (NYU), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Universidade do Porto = University of Porto, Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Physique du Globe de Paris (IPG Paris)-Centre National de la Recherche Scientifique (CNRS), University of Naples Federico II = Università degli studi di Napoli Federico II, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Stevanin, G, Santorelli, Fm, Azzedine, H, Coutinho, P, Chomilier, J, Denora, P, Martin, E, OUVRARD HERNANDEZ, Am, Tessa, A, Bouslam, N, Lossos, A, Charles, P, Loureiro, Jl, Elleuch, N, Confavreux, C, Cruz, Vt, Ruberg, M, Leguern, E, Grid, D, Tazir, M, Fontaine, B, Filla, Alessandro, Bertini, E, Durr, A, Brice, A., Université Mohammed V de Rabat [Agdal] (UM5), and 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)

Subjects
Genetic Linkage, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, MESH: Rats, Sprague-Dawley, MESH: Base Sequence, Corpus callosum, Corpus Callosum, Rats, Sprague-Dawley, MESH: Genotype, 0302 clinical medicine, MESH: Child, Chlorocebus aethiops, Spastic, MESH: Proteins, MESH: Animals, Age of Onset, MESH: DNA Mutational Analysis, Child, ComputingMilieux_MISCELLANEOUS, Genetics, Cerebral Cortex, 0303 health sciences, MESH: Spastic Paraplegia, Hereditary, Pedigree, MESH: COS Cells, COS Cells, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Paraplegia, Adult, MESH: Mutation, Adolescent, Genotype, MESH: Rats, MESH: Pedigree, MESH: Age of Onset, Molecular Sequence Data, Locus (genetics), Biology, MESH: Corpus Callosum, Frameshift mutation, 03 medical and health sciences, Chromosome 15, Genetic linkage, medicine, Animals, Humans, 030304 developmental biology, MESH: Adolescent, Chromosomes, Human, Pair 15, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, Spastic Paraplegia, Hereditary, Proteins, MESH: Adult, medicine.disease, MESH: Cercopithecus aethiops, MESH: Cerebral Cortex, Rats, nervous system diseases, MESH: Lod Score, Corticospinal tract, Mutation, Lod Score, MESH: Linkage (Genetics), 030217 neurology & neurosurgery, MESH: Chromosomes, Human, Pair 15
Abstract

Autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC) is a common and clinically distinct form of familial spastic paraplegia that is linked to the SPG11 locus on chromosome 15 in most affected families. We analyzed 12 ARHSP-TCC families, refined the SPG11 candidate interval and identified ten mutations in a previously unidentified gene expressed ubiquitously in the nervous system but most prominently in the cerebellum, cerebral cortex, hippocampus and pineal gland. The mutations were either nonsense or insertions and deletions leading to a frameshift, suggesting a loss-of-function mechanism. The identification of the function of the gene will provide insight into the mechanisms leading to the degeneration of the corticospinal tract and other brain structures in this frequent form of ARHSP.

Published
2007

17. Spastin mutations are frequent in sporadic spastic paraparesis and their spectrum is different from that observed in familial cases

Author

Sandrine Poëa-Guyon, Chantal M. E. Tallaksen, Bernard Bricka, Christel Depienne, Alexis Brice, Bertrand Fontaine, Jean-Yves Lephay, Alexandra Durr, Pierre Labauge, Neurologie et thérapeutique expérimentale, IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Affections de la Myeline et des Canaux Ioniques Musculaires, Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroradiologie [Hôpital Gui de Chauliac], Hôpital Gui de Chauliac [Montpellier], Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hôpital Gui de Chauliac [CHU Montpellier], and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)

Subjects
Proband, MESH: Mutation, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Paraplegia, Gene mutation, Spastin, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, MESH: Diagnosis, Differential, Genetics, Spastic, MESH: Adenosine Triphosphatases, MESH: Gene Frequency, Medicine, Missense mutation, MESH: Chromatography, High Pressure Liquid, Genetics (clinical), MESH: Spastin, 0303 health sciences, Mutation, MESH: Humans, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, business.industry, 030305 genetics & heredity, MESH: DNA, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, medicine.disease, Penetrance, 3. Good health, nervous system diseases, MESH: Paraparesis, Spastic, business, Paraplegia, MESH: Exons, Letter to JMG, 030217 neurology & neurosurgery
Abstract

Background: SPG4 encodes spastin, a member of the AAA protein family, and is the major gene responsible for autosomal dominant spastic paraplegia. It accounts for 10–40% of families with pure (or eventually complicated) hereditary spastic paraparesis (HSP). Objective: To assess the frequency of SPG4 mutation in patients with spastic paraplegia but without family histories. Methods: 146 mostly European probands with progressive spastic paraplegia were studied (103 with pure spastic paraplegia and 43 with additional features). Major neurological causes of paraplegia were excluded. None had a family history of paraplegia. DNA was screened by DHPLC for mutations in the 17 coding exons of the SPG4 gene. Sequence variants were characterised by direct sequencing. A panel of 600 control chromosomes was used to rule out polymorphisms. Results: The overall rate of mutations was 12%; 19 different mutations were identified in 18 patients, 13 of which were novel. In one family, where both parents were examined and found to be normal, the mutation was transmitted by the asymptomatic mother, indicating reduced penetrance. The parents of other patients were not available for analysis but were reported to be normal. There was no evidence for de novo mutations. The mutations found in these apparently isolated patients were mostly of the missense type and tended to be associated with a less severe phenotype than previously described in patients with inherited mutations. Conclusions: : The unexpected presence of SPG4 gene mutations in patients with sporadic spastic paraplegia suggests that gene testing should be done in individuals with pure or complicated spastic paraplegia without family histories.

Published
2005

18. Cultured peripheral neuroglial cells are highly permissive to sheep prion infection

Author

Didier Vilette, Annick Le Dur, Gregory Perrot, Christelle Langevin, Anne Baron-Van Evercooren, Hubert Laude, Corinne Bachelin, Olivier Andreoletti, Fabienne Archer, Nathalie Besnard, Jean-Luc Vilotte, Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), Affections de la Myeline et des Canaux Ioniques Musculaires, Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Interactions hôtes-agents pathogènes [Toulouse] (IHAP), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, and Unité de recherche Génétique Biochimique et Cytogénétique (LGBC)

Subjects
PrPSc Proteins, animal diseases, Immunology, Cell, Central nervous system, Mice, Transgenic, Scrapie, Biology, Microbiology, Virus, Mice, 03 medical and health sciences, 0302 clinical medicine, Antigen, Ganglia, Spinal, Virology, Peripheral Nervous System, medicine, Animals, PrPC Proteins, Cells, Cultured, 030304 developmental biology, Neurons, Infectivity, 0303 health sciences, Sheep, 3. Good health, nervous system diseases, medicine.anatomical_structure, Cell culture, Insect Science, Peripheral nervous system, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Pathogenesis and Immunity, Female, Schwann Cells, Neuroglia, 030217 neurology & neurosurgery
Abstract

Transmissible spongiform encephalopathies arise as a consequence of infection of the central nervous system (CNS) by prions. Spreading of the infectious agent through the peripheral nervous system (PNS) may represent a crucial step toward CNS neuroinvasion, but the modalities of this process have yet to be clarified. Here we provide further evidence that PNS glial cells are likely targets for infection by prions. Glial cell clones originating from dorsal root ganglia of transgenic mice expressing ovine PrP (tgOv) and simian virus 40 T antigen were found to be readily infectible by sheep scrapie agent. This led us to establish two stable cell lines that exhibited features of Schwann cells. These cells were shown to sustain an efficient and stable replication of sheep prion based on the high level of accumulation of abnormal PrP and infectivity in exposed cultures. We also provide evidence for abnormal PrP deposition in peripheral neuroglial cells from scrapie-infected tgOv mice and sheep. These findings have potential implications in terms of designing new cell systems permissive to prions and of peripheral pathobiology of prion infections.

Published
2004

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