2. Academic Validation
  3. X-linked primary immunodeficiency associated with hemizygous mutations in the moesin (MSN) gene

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

  • J Allergy Clin Immunol. 2016 Dec;138(6):1681-1689.e8. doi: 10.1016/j.jaci.2016.04.032.
Chantal Lagresle-Peyrou 1,  Sonia Luce 2,  Farid Ouchani 2,  Tayebeh Shabi Soheili 2,  Hanem Sadek 2,  Myriam Chouteau 2,  Amandine Durand 2,  Isabelle Pic 2,  Jacek Majewski 3,  Chantal Brouzes 4,  Nathalie Lambert 5,  Armelle Bohineust 6,  Els Verhoeyen 7,  François-Loïc Cosset 8,  Aude Magerus-Chatinet 9,  Frédéric Rieux-Laucat 9,  Virginie Gandemer 10,  Delphine Monnier 11,  Catherine Heijmans 12,  Marielle van Gijn 13,  Virgil A Dalm 14,  Nizar Mahlaoui 15,  Jean-Louis Stephan 16,  Capucine Picard 17,  Anne Durandy 2,  Sven Kracker 2,  Claire Hivroz 6,  Nada Jabado 18,  Geneviève de Saint Basile 19,  Alain Fischer 20,  Marina Cavazzana 1,  Isabelle André-Schmutz 21
Affiliations

Affiliations

  • 1 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.
  • 2 Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
  • 3 McGill University and Genome Québec Innovation Centre, Montreal, Quebec, Canada.
  • 4 Laboratory of Oncohematology, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
  • 5 Study Center for Primary Immunodeficiencies, Hôpital Necker Enfants-Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.
  • 6 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.
  • 7 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.
  • 8 CIRI, International Center for Infectiology Research, EVIR group, INSERM U1111, CNRS, Université de Lyon-1, Lyon, France.
  • 9 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.
  • 10 Unité d'hémato-oncologie et greffes de moelle, CHU Rennes, CNRS UMR 6290, Université de Rennes 1, Rennes, France.
  • 11 Service d'Immunologie, Thérapie Cellulaire et Hématopoièse, CHU Rennes, Rennes, France.
  • 12 Centre Hospitalier de Jolimont, La Louvière, Belgium; Hôpital Universitaire des enfants Reine Fabiola, Brussels, Belgium.
  • 13 Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
  • 14 Departments of Internal Medicine and Immunology, Erasmus Medical Center, Rotterdam, The Netherlands.
  • 15 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.
  • 16 Service de Pédiatrie, CHU Nord, Saint-Étienne, France.
  • 17 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.
  • 18 McGill University and Genome Québec Innovation Centre, Montreal, Quebec, Canada; Department of Pediatrics, McGill University, McGill University Health Center, Montreal, Quebec, Canada.
  • 19 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.
  • 20 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.
  • 21 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.
PMID: 27405666 DOI: 10.1016/j.jaci.2016.04.032
Abstract

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.

Keywords

Leukopenia; adhesion; ezrin-radixin-moesin protein; migration; moesin; primary immunodeficiency.

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