title: X-linked primary immunodeficiency associated with hemizygous mutations in the moesin (MSN) gene.
abstract: 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.
  
  
  
  We sought to characterize the genetic defect involved in a new form of X-linked immunodeficiency.
  
  
  
  We performed genetic analyses and an exhaustive phenotypic and functional characterization of the lymphocyte compartment.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Biotherapy Clinical Investigation Center, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Lagresle-Peyrou
authors.affiliation: Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Luce
authors.affiliation: Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
authors.forename: Farid
authors.initials: F
authors.lastname: Ouchani
authors.affiliation: Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
authors.forename: Tayebeh Shabi
authors.initials: TS
authors.lastname: Soheili
authors.affiliation: Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
authors.forename: Hanem
authors.initials: H
authors.lastname: Sadek
authors.affiliation: Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Chouteau
authors.affiliation: Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Durand
authors.affiliation: Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Pic
authors.affiliation: McGill University and Genome Québec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Laboratory of Oncohematology, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Brouzes
authors.affiliation: Study Center for Primary Immunodeficiencies, Hôpital Necker Enfants-Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lambert
authors.affiliation: Institut Curie, Centre de Recherche, Pavillon Pasteur, Paris, France; Institut National de la Santé et de la Recherche Médicale, Unité 932, Immunité et Cancer, Paris, France.
authors.forename: Armelle
authors.initials: A
authors.lastname: Bohineust
authors.affiliation: CIRI, International Center for Infectiology Research, EVIR group, INSERM U1111, CNRS, Université de Lyon-1, Lyon, France; INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), équipe "contrôle métabolique des morts cellulaires," Nice, France.
authors.forename: Els
authors.initials: E
authors.lastname: Verhoeyen
authors.affiliation: CIRI, International Center for Infectiology Research, EVIR group, INSERM U1111, CNRS, Université de Lyon-1, Lyon, France.
authors.forename: François-Loïc
authors.initials: FL
authors.lastname: Cosset
authors.affiliation: Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Laboratory of Immunogenetics of Pediatric Autoimmunity, INSERM UMR 1163, Necker Children's Hospital, Paris, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Magerus-Chatinet
authors.affiliation: Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Laboratory of Immunogenetics of Pediatric Autoimmunity, INSERM UMR 1163, Necker Children's Hospital, Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Rieux-Laucat
authors.affiliation: Unité d'hémato-oncologie et greffes de moelle, CHU Rennes, CNRS UMR 6290, Université de Rennes 1, Rennes, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Gandemer
authors.affiliation: Service d'Immunologie, Thérapie Cellulaire et Hématopoièse, CHU Rennes, Rennes, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Monnier
authors.affiliation: Centre Hospitalier de Jolimont, La Louvière, Belgium; Hôpital Universitaire des enfants Reine Fabiola, Brussels, Belgium.
authors.forename: Catherine
authors.initials: C
authors.lastname: Heijmans
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marielle
authors.initials: M
authors.lastname: van Gijn
authors.affiliation: Departments of Internal Medicine and Immunology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Virgil A
authors.initials: VA
authors.lastname: Dalm
authors.affiliation: Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Pediatric Immunology Haematology and Rheumatology Unit, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Nizar
authors.initials: N
authors.lastname: Mahlaoui
authors.affiliation: Service de Pédiatrie, CHU Nord, Saint-Étienne, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Stephan
authors.affiliation: Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Study Center for Primary Immunodeficiencies, Hôpital Necker Enfants-Malades, Assistance Publique-Hôpitaux de Paris, Paris, France; French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Pediatric Immunology Haematology and Rheumatology Unit, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.affiliation: Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
authors.affiliation: Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
authors.forename: Sven
authors.initials: S
authors.lastname: Kracker
authors.affiliation: Institut Curie, Centre de Recherche, Pavillon Pasteur, Paris, France; Institut National de la Santé et de la Recherche Médicale, Unité 932, Immunité et Cancer, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Hivroz
authors.affiliation: McGill University and Genome Québec Innovation Centre, Montreal, Quebec, Canada; Department of Pediatrics, McGill University, McGill University Health Center, Montreal, Quebec, Canada.
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.affiliation: Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Study Center for Primary Immunodeficiencies, Hôpital Necker Enfants-Malades, Assistance Publique-Hôpitaux de Paris, Paris, France; INSERM Unité U1163, Normal and Pathological Homeostasis of the Immune System, Hôpital Necker Enfants-Malades, Paris, France.
authors.forename: Geneviève
authors.initials: G
authors.lastname: de Saint Basile
authors.affiliation: Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Pediatric Immunology Haematology and Rheumatology Unit, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; INSERM Unité U1163, Hôpital Necker Enfants-Malades, Paris, France; Collège de France, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.affiliation: Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Biotherapy Clinical Investigation Center, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Marina
authors.initials: M
authors.lastname: Cavazzana
authors.affiliation: Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Biotherapy Clinical Investigation Center, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France. Electronic address: isabelle.andre-schmutz@inserm.fr.
authors.forename: Isabelle
authors.initials: I
authors.lastname: André-Schmutz
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002448:Cell Adhesion; D002465:Cell Movement; D002648:Child; D002675:Child, Preschool; D041321:Chromosomes, Human, X / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D007239:Infections / Q000235:genetics*; D018655:Lymphocyte Count; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree
chemical_list: D008840:Microfilament Proteins; C071058:moesin
keywords: Leukopenia; adhesion; ezrin-radixin-moesin protein; migration; moesin; primary immunodeficiency