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

Chantal Lagresle-Peyrou (1, 2) , Sonia Luce (1) , Farid Ouchani (1) , Tayebeh Shabi Soheili (1) , Hanem Sadek (1) , Myriam Chouteau (1) , Amandine Durand (1) , Isabelle Pic (1) , Jacek Majewski (3) , Chantal Brouzes (4) , Nathalie Lambert (5) , Armelle Bohineust (6) , Els Verhoeyen (7, 8) , Cosset François-Loïc (8) , Aude Magérus-Chatinet (9) , Frédéric Rieux-Laucat (9) , Virginie Gandemer (10, 11) , Delphine Monnier (12) , Catherine Heijmans (13) , Marielle Van Gijn (14) , Virgil A. Dalm (15) , Nizar Mahlaoui (16, 17, 18) , Jean-Louis Stephan (19) , Capucine Picard (16, 17, 18) , Anne Durandy (1) , Sven Kracker (1) , Claire Hivroz (6) , Nada Jabado (20) , Geneviève De Saint Basile (17) , Alain Fischer (16, 17, 18, 21) , Marina Cavazzana (1, 2) , Isabelle André-Schmutz (1, 2)

1 Equipe Inserm U1163 - Human Lymphohematopoiesis Laboratory
2 Département de Biothérapie [CHU Necker]
3 McGill University and Genome Quebec Innovation Centre
4 CHU Necker - Enfants Malades [AP-HP]
5 Center for the Study of Primary Immunodeficiencies [Paris]
6 U932 - Immunité et cancer
7 C3M - Centre méditerranéen de médecine moléculaire
8 EVIR - Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy
9 Equipe Inserm U1163 - Immunogenetics of pediatric autoimmune diseases
10 IGDR - Institut de Génétique et Développement de Rennes
11 CHU Pontchaillou [Rennes]
12 HITC - Service d'Hématologie, Immunologie et de Thérapie Cellulaire
13 HUDERF - Hôpital Universitaire des Enfants Reine Fabiola [Bruxelles, Belgique]
14 Dpt of Genetics [Utrecht]
15 Department of Internal Medicine
16 CEREDIH - Centre de Référence Déficits Immunitaires Héréditaires
17 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
18 Service d'immuno-hématologie pédiatrique [CHU Necker]
19 CHU Saint-Etienne
20 the Genome Quebec Innovation Centre
21 Collège de France - Chaire Médecine expérimentale (A. Fischer)

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

Domains: Life Sciences [q-bio]; Genetics

Chantal Lagresle-Peyrou, Sonia Luce, Farid Ouchani, Tayebeh Shabi Soheili, Hanem Sadek, et al.. X-linked primary immunodeficiency associated with hemizygous mutations in the moesin (MSN) gene. Journal of Allergy and Clinical Immunology, 2016, 138 (6), pp.1681-1689.e8. ⟨10.1016/j.jaci.2016.04.032⟩. ⟨hal-01439360⟩