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

Chantal Lagresle-Peyrou; Sonia Luce; Farid Ouchani; Tayebeh Shabi Soheili; Hanem Sadek; Myriam Chouteau; Amandine Durand; Isabelle Pic; Jacek Majewski; Chantal Brouzes; Nathalie Lambert; Armelle Bohineust; Els Verhoeyen; François-Loïc Cosset; Aude Magerus-Chatinet; Frédéric Rieux-Laucat; Virginie Gandemer; Delphine Monnier; Catherine Heijmans; Marielle van Gijn; Virgil A Dalm; Nizar Mahlaoui; Jean-Louis Stephan; Capucine Picard; Anne Durandy; Sven Kracker; Claire Hivroz; Nada Jabado; Geneviève de Saint Basile; Alain Fischer; Marina Cavazzana; Isabelle André-Schmutz

doi:10.1016/j.jaci.2016.04.032

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. Epub 2016 Jun 4.

Authors

Chantal Lagresle-Peyrou¹, Sonia Luce², Farid Ouchani², Tayebeh Shabi Soheili², Hanem Sadek², Myriam Chouteau², Amandine Durand², Isabelle Pic², Jacek Majewski³, Chantal Brouzes⁴, Nathalie Lambert⁵, Armelle Bohineust⁶, Els Verhoeyen⁷, François-Loïc Cosset⁸, Aude Magerus-Chatinet⁹, Frédéric Rieux-Laucat⁹, Virginie Gandemer¹⁰, Delphine Monnier¹¹, Catherine Heijmans¹², Marielle van Gijn¹³, Virgil A Dalm¹⁴, Nizar Mahlaoui¹⁵, Jean-Louis Stephan¹⁶, Capucine Picard¹⁷, Anne Durandy², Sven Kracker², Claire Hivroz⁶, Nada Jabado¹⁸, Geneviève de Saint Basile¹⁹, Alain Fischer²⁰, Marina Cavazzana¹, Isabelle André-Schmutz²¹

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.

MeSH terms

Adolescent
Adult
Aged
CD8-Positive T-Lymphocytes / immunology*
Cell Adhesion
Cell Movement
Child
Child, Preschool
Chromosomes, Human, X / genetics*
Genetic Association Studies
Humans
Immunologic Deficiency Syndromes / genetics*
Infections / genetics*
Lymphocyte Count
Male
Microfilament Proteins / genetics*
Mutation / genetics*
Pedigree

Substances

Microfilament Proteins
moesin