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
  • 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: [email protected].
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.