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1. Alternative UNC13D Promoter Encodes a Functional Munc13-4 Isoform Predominantly Expressed in Lymphocytes and Platelets

Author

Donatella Galgano, Tayebeh Soheili, Matthias Voss, Lamberto Torralba-Raga, Bianca Tesi, Frank Cichocki, Isabelle Andre, Jens Rettig, Marina Cavazzana, and Yenan Bryceson

Subjects
UNC13D, primary immunodeficiency, familial hemophagocytic lymphohistiocytosis type 3, intronic mutation, alternative intronic promoter/isoform, lymphocyte cytotoxicity, Immunologic diseases. Allergy, RC581-607
Abstract

Autosomal recessive mutations in genes required for cytotoxicity are causative of a life-threatening, early-onset hyperinflammatory syndrome termed familial hemophagocytic lymphohistiocytosis (FHL). Mutations in UNC13D cause FHL type 3. UNC13D encodes Munc13-4, a member of the Unc13 protein family which control SNARE complex formation and vesicle fusion. We have previously identified FHL3-associated mutations in the first intron of UNC13D which control transcription from an alternative transcriptional start site. Using isoform specific antibodies, we demonstrate that this alternative Munc13-4 isoform with a unique N-terminus is preferentially expressed in human lymphocytes and platelets, as compared to the conventional isoform that was mostly expressed in monocytes and neutrophils. The distinct N-terminal of the two isoforms did not impact on Munc13-4 localization or trafficking to the immunological synapse of cytotoxic T cells. Moreover, ectopic expression of both isoforms efficiently restored exocytosis by FHL3 patient-derived Munc13-4 deficient T cells. Thus, we demonstrate that the conventional and alternative Munc13-4 isoforms have different expression pattern in hematopoietic cell subsets, but display similar localization and contribution to T cell exocytosis. The use of an alternative transcriptional starting site (TSS) in lymphocytes and platelets could be selected for increasing the overall levels of Munc13-4 expression for efficient secretory granule release.

Published
2020
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2. A Nontoxic Transduction Enhancer Enables Highly Efficient Lentiviral Transduction of Primary Murine T Cells and Hematopoietic Stem Cells

Author

Marianne Delville, Tayebeh Soheili, Florence Bellier, Amandine Durand, Adeline Denis, Chantal Lagresle-Peyrou, Marina Cavazzana, Isabelle Andre-Schmutz, and Emmanuelle Six

Subjects
Genetics, QH426-470, Cytology, QH573-671
Abstract

Lentiviral vectors have emerged as an efficient, safe therapeutic tool for gene therapy based on hematopoietic stem cells (HSCs) or T cells. However, the monitoring of transduced cells in preclinical models remains challenging because of the inefficient transduction of murine primary T cells with lentiviral vectors, in contrast to gammaretroviral vectors. The use of this later in preclinical proof of concept is not considered as relevant when a lentiviral vector will be used in a clinical trial. Hence, there is an urgent need to develop an efficient transduction protocol for murine cells with lentiviral vectors. Here, we describe an optimized protocol in which a nontoxic transduction enhancer (Lentiboost) enables the efficient transduction of primary murine T cells with lentiviral vectors. The optimized protocol combines low toxicity and high transduction efficiency. We achieved a high-level transduction of murine CD4+ and CD8+ T cells with a VSV-G-pseudotyped lentiviral vector with no changes in the phenotypes of transduced T cells, which were stable and long-lived in culture. This enhancer also increased the transduction of murine HSCs. Hence, use of this new transduction enhancer overcomes the limitations of lentiviral vectors in preclinical experiments and should facilitate the translation of strategies based on lentiviral vectors from the bench to the clinic. Keywords: murine CD4+ T cells, murine CD8+ T cells, murine Sca1+ cells, lentiviral transduction, Lentiboost, gene therapy

Published
2018
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3. Gene transfer into hematopoietic stem cells reduces HLH manifestations in a murine model of Munc13-4 deficiency

Author

Tayebeh Soheili, Amandine Durand, Fernando E. Sepulveda, Julie Rivière, Chantal Lagresle-Peyrou, Hanem Sadek, Geneviève de Saint Basile, Samia Martin, Fulvio Mavilio, Marina Cavazzana, and Isabelle André-Schmutz

Subjects
Specialties of internal medicine, RC581-951
Abstract

Abstract: Patients with mutations in the UNC13D gene (coding for Munc13-4 protein) suffer from familial hemophagocytic lymphohistiocytosis type 3 (FHL3), a life-threatening immune and hyperinflammatory disorder. The only curative treatment is allogeneic hematopoietic stem cell (HSC) transplantation, although the posttreatment survival rate is not satisfactory. Here, we demonstrate the curative potential of UNC13D gene correction of HSCs in a murine model of FHL3. We generated a self-inactivating lentiviral vector, used it to complement HSCs from Unc13d-deficient (Jinx) mice, and transplanted the cells back into the irradiated Jinx recipients. This procedure led to complete reconstitution of the immune system (ie, to wild-type levels). The recipients were then challenged with lymphocytic choriomeningitis virus to induce hemophagocytic lymphohistiocytosis (HLH)–like manifestations. All the clinical and biological signs of HLH were significantly reduced in mice having undergone HSC UNC13D gene correction than in nontreated animals. This beneficial effect was evidenced by the correction of blood cytopenia, body weight gain, normalization of the body temperature, decreased serum interferon-γ level, recovery of liver damage, and decreased viral load. These improvements can be explained by the restoration of the CD8+ T lymphocytes' cytotoxic function (as demonstrated here in an in vitro degranulation assay). Overall, our results demonstrate the efficacy of HSC gene therapy in an FHL-like setting of immune dysregulation.

Published
2017
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4. Severe hematopoietic stem cell inflammation compromises chronic granulomatous disease gene therapy

Author

Steicy Sobrino, Alessandra Magnani, Michaela Semeraro, Loredana Martignetti, Akira Cortal, Adeline Denis, Chloé Couzin, Capucine Picard, Jacinta Bustamante, Elisa Magrin, Laure Joseph, Cécile Roudaut, Aurélie Gabrion, Tayebeh Soheili, Corinne Cordier, Olivier Lortholary, François Lefrere, Frédéric Rieux-Laucat, Jean-Laurent Casanova, Sylvain Bodard, Nathalie Boddaert, Adrian J. Thrasher, Fabien Touzot, Sophie Taque, Felipe Suarez, Ambroise Marcais, Agathe Guilloux, Chantal Lagresle-Peyrou, Anne Galy, Antonio Rausell, Stephane Blanche, Marina Cavazzana, and Emmanuelle Six

Subjects
General Biochemistry, Genetics and Molecular Biology
Published
2023
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5. Ex Vivo Production of Large Numbers of Genetically Modified NK Cells from Cord Blood or Mobilized Peripheral Blood CD34 + Cells Using Notch Ligand Delta-like 4 Culture System

Author

Pierre Gaudeaux, Tayebeh Soheili, Ranjita Devi Moirangthem, Chantal Lagresle-Peyrou, Isabelle André, Akshay Joshi, and Marina Cavazzana

Subjects
Chemistry, Cd34 cells, Cord blood, Immunology, Cell Biology, Hematology, Notch ligand, Biochemistry, Delta like 1, Ex vivo, Peripheral blood, Genetically modified organism, Cell biology
Abstract

Natural killer (NK) cells are an essential component of human innate immune, with a remarkable ability to provide protection against cancer and viral infections. NK-based immune therapy has several advantages over T cell immunotherapy: NK cells do not cause graft-versus-host disease and do not induce T-cell driven inflammatory cytokine storm. Moreover, unlike T cell, NK cells do not need prior sensitization, specific antigen recognition and clonal expansion for their cytotoxic effector functions and they can rapidly trigger cytotoxicity against their targets. NK cells can be expanded from multiple sources including peripheral blood mononuclear cells (PBMCs), umbilical cord blood (UCB), or mobilized peripheral blood (mPB) CD34 + cells. Yet the lack of efficient methods for in-vitro NK cell expansion, purification and genetic modification limits the clinical use of NK cell therapy. We aimed at developing a simple, scalable and clinically feasible technique for therapeutic NK cell production based on our recently published culture system that can produce large numbers of unmodified or genetically modified CD7 + T lymphoid progenitors from UCB and mPB CD34 + cells in 7 days on immobilized Notch-ligand delta-like 4 recombinant protein DLL4. Since T cells and NK cells share a common T/NK cell progenitor, we are interested to investigate the NK cell potential of DLL4 culture-generated T lymphoid progenitors. Firstly, we tested the NK cell potential of the transduced or non- transduced UCB or mPB CD34 +-derived progenitors from DLL4 culture by subjecting them to a feeder free NK cell differentiation for 3 weeks. HSPC-derived progenitors can be efficiently transduced with lentiviral vectors (average transduction efficacy: 50%). The transduced/ non-transduced progenitors were able to efficiently differentiate into NK (CD3 -CD56 +) cells beginning from one week of differentiation, reaching a frequencies of NK cells of >90% without any detectable T cell contamination at week 2. The phenotypic characterization of the NK cells demonstrates the presence of activation receptors such as NKG2D, DNAM-1, NKp30, NKp44 and NKp46 while lacking the inhibitory receptors like KLRG1, KIR2DL2/DL3 and KIR3DL1/DL2. Interestingly, these cells express the transcription factors known to be essential for NK cell differentiation and functions such as Eomes, T-bet and ID2. Additionally, the CB or mPB HSPC-derived NK cells (both transduced/ non-transduced) express perforin and granzyme B reflecting their ability to show cytotoxic potential. Further, the stimulation of UCB or mPB derived NK cells with myelogenous leukemia cell line K562 cells showed high level of degranulation, which is the key step for Interferon gamma (IFNg) induction. An analysis cytotoxic activity of the CB or mPB derived NK cells against K562 cells and monocytic leukemia cell line THP1 cells showed their ability to efficiently kill K562 cells compared to THP1 cells, however the UCB derived NK cells were highly cytotoxic compared to mPB derived NK cells. These data suggests that our DLL4 culture system, along with feeder-free NK cell differentiation is a unique combination that is able to give rise to high number of pure NK cell population with high cytotoxic potential. These results lay a foundation towards an easier approach to NK cell therapy for effective treatment of cancers and viral infections, which will be developed in collaboration with Smart Immune Inc. Disclosures Cavazzana: Smart Immune: Other: co-founder.

Published
2021
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6. Alternative

Author

Donatella, Galgano, Tayebeh, Soheili, Matthias, Voss, Lamberto, Torralba-Raga, Bianca, Tesi, Frank, Cichocki, Isabelle, Andre, Jens, Rettig, Marina, Cavazzana, and Yenan, Bryceson

Subjects
Blood Platelets, familial hemophagocytic lymphohistiocytosis type 3, Immunology, Membrane Proteins, UNC13D, primary immunodeficiency, Lymphohistiocytosis, Hemophagocytic, lymphocyte cytotoxicity, Mutation, Humans, Protein Isoforms, Lymphocytes, Promoter Regions, Genetic, intronic mutation, alternative intronic promoter/isoform, Cells, Cultured, T-Lymphocytes, Cytotoxic, Original Research
Abstract

Autosomal recessive mutations in genes required for cytotoxicity are causative of a life-threatening, early-onset hyperinflammatory syndrome termed familial hemophagocytic lymphohistiocytosis (FHL). Mutations in UNC13D cause FHL type 3. UNC13D encodes Munc13-4, a member of the Unc13 protein family which control SNARE complex formation and vesicle fusion. We have previously identified FHL3-associated mutations in the first intron of UNC13D which control transcription from an alternative transcriptional start site. Using isoform specific antibodies, we demonstrate that this alternative Munc13-4 isoform with a unique N-terminus is preferentially expressed in human lymphocytes and platelets, as compared to the conventional isoform that was mostly expressed in monocytes and neutrophils. The distinct N-terminal of the two isoforms did not impact on Munc13-4 localization or trafficking to the immunological synapse of cytotoxic T cells. Moreover, ectopic expression of both isoforms efficiently restored exocytosis by FHL3 patient-derived Munc13-4 deficient T cells. Thus, we demonstrate that the conventional and alternative Munc13-4 isoforms have different expression pattern in hematopoietic cell subsets, but display similar localization and contribution to T cell exocytosis. The use of an alternative transcriptional starting site (TSS) in lymphocytes and platelets could be selected for increasing the overall levels of Munc13-4 expression for efficient secretory granule release.

Published
2020

7. Gene-corrected human Munc13-4–deficient CD8+ T cells can efficiently restrict EBV-driven lymphoproliferation in immunodeficient mice

Author

Geneviève de Saint Basile, Persis Amrolia, Amandine Durand, Julie Rivière, François-Loïc Cosset, Ida Ricciardelli, Chantal Lagresle-Peyrou, Isabelle André-Schmutz, Tayebeh Soheili, Marina Cavazzana, Anne-Céline Derrien, and Els Verhoeyen

Subjects
0301 basic medicine, Epstein-Barr Virus Infections, Herpesvirus 4, Human, Immunology, Lymphoproliferative disorders, Mice, SCID, CD8-Positive T-Lymphocytes, Biochemistry, Lymphohistiocytosis, Hemophagocytic, Mice, 03 medical and health sciences, Transduction, Genetic, Animals, Humans, Medicine, Cytotoxic T cell, Gene, Epstein–Barr virus infection, business.industry, Membrane Proteins, FHL3, Genetic Therapy, Cell Biology, Hematology, Familial Hemophagocytic Lymphohistiocytosis, medicine.disease, Lymphoproliferative Disorders, 030104 developmental biology, Membrane protein, UNC13D Gene, business
Abstract

To the editor: Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) is a hyperinflammatory disease caused by mutations in the UNC13D gene (coding for the Munc13-4 protein); FHL3 accounts for 30% to 35% of FHL cases.[1][1] In cytotoxic T cells (CTLs) and natural killer cells, Munc13-4 helps to

Published
2016
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8. X-linked primary immunodeficiency associated with hemizygous mutations in the moesin (MSN) gene

Author

Jacek Majewski, Marielle E. van Gijn, Alain Fischer, Geneviève de Saint Basile, Capucine Picard, Nada Jabado, Els Verhoeyen, Sonia Luce, Tayebeh Soheili, Nathalie Lambert, Amandine Durand, Armelle Bohineust, Claire Hivroz, Virginie Gandemer, Farid Ouchani, Chantal Brouzes, Catherine Heijmans, Anne Durandy, Isabelle Pic, Myriam Chouteau, Marina Cavazzana, Virgil A. S. H. Dalm, Nizar Mahlaoui, Aude Magerus-Chatinet, François-Loïc Cosset, Isabelle André-Schmutz, Delphine Monnier, Sven Kracker, Chantal Lagresle-Peyrou, Jean-Louis Stephan, Frédéric Rieux-Laucat, Hanem Sadek, Human Lymphohematopoiesis Laboratory (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Biothérapie [CHU Necker], CHU Necker - Enfants Malades [AP-HP]-Université Paris Descartes - Paris 5 (UPD5)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), McGill University and Genome Quebec Innovation Centre, CHU Necker - Enfants Malades [AP-HP], Center for the Study of Primary Immunodeficiencies [Paris], Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (Equipe EVIR), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), 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 ), CHU Pontchaillou [Rennes], Service d'Hématologie, Immunologie et de Thérapie Cellulaire (HITC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Hôpital Universitaire des Enfants - Reine Fabiola, Dpt of Genetics [Utrecht], University Medical Center [Utrecht], Department of Internal Medicine, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immuno-hématologie pédiatrique [CHU Necker], CHU Saint-Etienne, the Genome Quebec Innovation Centre, McGill University, Collège de France (CdF), French National Research Agency, French National Institute of Health and Medical Research (INSERM), La Ligue contre le Cancer and La Fondation ARC pour la Recherche sur le Cancer, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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 Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université 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 ), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Hôpital Universitaire des Enfants Reine Fabiola [Bruxelles, Belgique] (HUDERF), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), McGill University = Université McGill [Montréal, Canada], Collège de France - Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), CIC-BT 502 INSERM, Departement de Biotherapie, Laboratoire d'hématologie ( ERL 8254 ), 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 ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Référence Déficits Immunitaires Héréditaires ( CEREDIH ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre méditérannéen de médecine moléculaire ( C3M ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ), Centre International de Recherche en Infectiologie ( CIRI ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), 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 ), Service d'Hématologie, Immunologie et de Thérapie Cellulaire ( HITC ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Collège de France ( CdF ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Chaire Médecine expérimentale (A. Fischer), 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)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Institut Curie-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunology, and Internal Medicine

Subjects
Adult, Male, 0301 basic medicine, Adolescent, Moesin, Immunology, Nonsense mutation, macromolecular substances, CD8-Positive T-Lymphocytes, Biology, Infections, primary immunodeficiency, migration, medicine.disease_cause, ezrin-radixin-moesin protein, Hypogammaglobulinemia, 03 medical and health sciences, Cell Movement, Radixin, Cell Adhesion, Journal Article, medicine, Humans, Immunology and Allergy, Missense mutation, Lymphocyte Count, Child, moesin, Genetic Association Studies, Immunodeficiency, Aged, Chromosomes, Human, X, [SDV.GEN]Life Sciences [q-bio]/Genetics, Mutation, Microfilament Proteins, Immunologic Deficiency Syndromes, Leukopenia, medicine.disease, Pedigree, 3. Good health, adhesion, 030104 developmental biology, Child, Preschool, Cancer research, Primary immunodeficiency, [ SDV.GEN ] Life Sciences [q-bio]/Genetics
Abstract

International audience; BACKGROUND: We investigated 7 male patients (from 5 different families) presenting with profound lymphopenia, hypogammaglobulinemia, fluctuating monocytopenia and neutropenia, a poor immune response to vaccine antigens, and increased susceptibility to bacterial and varicella zoster virus infections. OBJECTIVE: We sought to characterize the genetic defect involved in a new form of X-linked immunodeficiency. METHODS: We performed genetic analyses and an exhaustive phenotypic and functional characterization of the lymphocyte compartment. RESULTS: We observed hemizygous mutations in the moesin (MSN) gene (located on the X chromosome and coding for MSN) in all 7 patients. Six of the latter had the same missense mutation, which led to an amino acid substitution (R171W) in the MSN four-point-one, ezrin, radixin, moesin domain. The seventh patient had a nonsense mutation leading to a premature stop codon mutation (R533X). The naive T-cell counts were particularly low for age, and most CD8(+) T cells expressed the senescence marker CD57. This phenotype was associated with impaired T-cell proliferation, which was rescued by expression of wild-type MSN. MSN-deficient T cells also displayed poor chemokine receptor expression, increased adhesion molecule expression, and altered migration and adhesion capacities. CONCLUSION: Our observations establish a causal link between an ezrin-radixin-moesin protein mutation and a primary immunodeficiency that could be referred to as X-linked moesin-associated immunodeficiency.

Published
2016
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9. Rescue of Sarcoglycan Mutations by Inhibition of Endoplasmic Reticulum Quality Control is Associated with Minimal Structural Modifications

Author

Marc Bartoli, Evelyne Gicquel, Florence Le Roy, Isabelle Richard, Tayebeh Soheili, Luu N'Guyen, Jérôme Poupiot, Généthon, Laboratoire Analyse et Modélisation pour la Biologie et l'Environnement (LAMBE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Université d'Évry-Val-d'Essonne (UEVE)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Université Paris-Seine-Université Paris-Seine-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Muscle disorder, Biology, Endoplasmic Reticulum, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Alkaloids, Sarcolemma, Mutant protein, Sarcoglycans, Genetics, medicine, Sarcoglycanopathies, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Enzyme Inhibitors, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Endoplasmic reticulum, ER retention, medicine.disease, Cell biology, Sarcoglycan, Protein Transport, HEK293 Cells, Biochemistry, Kifunensine, chemistry, Mutation, 030217 neurology & neurosurgery, Limb-girdle muscular dystrophy, HeLa Cells
Abstract

International audience; Sarcoglycanopathies (SGP) are a group of autosomal recessive muscle disorders caused by primary mutations in one of the four sarcoglycan genes. The sarcoglycans (alpha-, beta-, gamma-, and delta-sarcoglycan) form a tetrameric complex at the muscle membrane that is part of the dystrophin-glycoprotein complex and plays an essential role for membrane integrity during muscle contractions. We previously showed that the most frequent missense mutation in alpha-sarcoglycan (p.R77C) leads to the absence of the protein at the cell membrane due to its blockade by the endoplasmic reticulum (ER) quality control. Moreover, we demonstrated that inhibition of the ER alpha-mannosidase I activity using kifunensine could rescue the mutant protein localization at the cell membrane. Here, we investigate 25 additional disease-causing missense mutations in the sarcoglycan genes with respect to intracellular fate and localization rescue of the mutated proteins by kifunensine. Our studies demonstrate that, similarly to p.R77C, 22 of 25 of the selected mutations lead to defective intracellular trafficking of the SGs proteins. Six of these were saved from ER retention upon kifunensine treatment. The trafficking of SGs mutants rescued by kifunensine was associated with mutations that have moderate structural impact on the protein. Hum Mutat 33:429-439, 2012. (C) 2011 Wiley Periodicals, Inc.

Published
2012
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10. Mannosidase I inhibition rescues the human alpha-sarcoglycan R77C recurrent mutation

Author

Bjarne Udd, Laetitia Barrault, Marie Malissen, Isabelle Richard, Tayebeh Soheili, Norma Perez, Marc Bartoli, Bernard Malissen, Evelyne Gicquel, Olivier Danos, Nathalie Vincent-Lacaze, Généthon, Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Neurological Department, Vaasa Central Hospital, and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Mannosidase, MESH: Muscles, Leupeptins, medicine.disease_cause, MESH: Muscular Dystrophy, Animal, MESH: Mice, Knockout, Mice, 0302 clinical medicine, Missense mutation, MESH: Animals, Muscular dystrophy, Genetics (clinical), Cellular localization, Mice, Knockout, 0303 health sciences, Mutation, Muscles, General Medicine, 16. Peace & justice, 3. Good health, Sarcoglycan, Protein Transport, Phenotype, Biochemistry, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH: Protein Transport, MESH: Cell Line, Tumor, MESH: Muscular Dystrophies, Limb-Girdle, Mutation, Missense, Biology, MESH: Phenotype, 03 medical and health sciences, Alkaloids, MESH: Mannosidases, MESH: Alkaloids, Cell Line, Tumor, Sarcoglycans, Mannosidases, Genetics, medicine, Animals, Humans, Cysteine, MESH: Sarcoglycans, Molecular Biology, MESH: Mice, 030304 developmental biology, SGCA, MESH: Mutation, Missense, MESH: Humans, MESH: Leupeptins, Muscular Dystrophy, Animal, MESH: Cysteine, medicine.disease, Molecular biology, Muscular Dystrophies, Limb-Girdle, MESH: Female, 030217 neurology & neurosurgery, Limb-girdle muscular dystrophy
Abstract

International audience; Limb girdle muscular dystrophy type 2D (LGMD2D, OMIM600119) is a genetic progressive myopathy that is caused by mutations in the human alpha-sarcoglycan gene (SGCA). Here, we have introduced in mice the most prevalent LGMD2D mutation, R77C. It should be noted that the natural murine residue at this position is a histidine. The model is, therefore, referred as Sgca(H77C/H77C). Unexpectedly, we observed an absence of LGMD2D-like phenotype at histological or physiological level. Using a heterologous cellular model of the sarcoglycan complex formation, we showed that the R77C allele encodes a protein that fails to be delivered to its proper cellular localization in the plasma membrane, and consequently to the disappearance of a positively charged residue. Subsequently, we transferred an AAV vector coding for the human R77C protein in the muscle of Sgca-null mice and were able to pharmacologically rescue the R77C protein from endoplasmic reticulum-retention using proteasome or mannosidase I inhibitors. This suggests a therapeutic approach for LGMD2D patients carrying mutations that impair alpha-sarcoglycan trafficking.

Published
2008
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