X-linked primary immunodeficiency associated with hemizygous mutations in the moesin (MSN) gene - 18/04/17

Doi : 10.1016/j.jaci.2016.04.032

Chantal Lagresle-Peyrou, PhD ^a,^b,^c, Sonia Luce, MSc ^a,^b, Farid Ouchani, PhD ^a,^b, Tayebeh Shabi Soheili, PhD ^a,^b, Hanem Sadek, MSc ^a,^b, Myriam Chouteau, MSc ^a,^b, Amandine Durand, MSc ^a,^b, Isabelle Pic, MSc ^a,^b, Jacek Majewski, PhD ^d, Chantal Brouzes, MD ^e, Nathalie Lambert, MSc ^f, Armelle Bohineust, PhD ^g,^h, Els Verhoeyen, PhD ^i,^j, François-Loïc Cosset, PhD ⁱ, Aude Magerus-Chatinet, PhD ^b,^k, Frédéric Rieux-Laucat, PhD ^b,^k, Virginie Gandemer, MD, PhD ^l, Delphine Monnier, PhD ^m, Catherine Heijmans, MD ^n,^o, Marielle van Gijn, PhD ^p, Virgil A. Dalm, MD ^q, Nizar Mahlaoui, MD, MSc ^b,^r,^s,^t, Jean-Louis Stephan, MD ^u, Capucine Picard, MD, PhD ^b,^f,^r,^s,^t, Anne Durandy, MD, PhD ^a,^b, Sven Kracker, PhD ^a,^b, Claire Hivroz, PhD ^g,^h, Nada Jabado, MD, PhD ^d,^v, Geneviève de Saint Basile, MD, PhD ^b,^f,^w, Alain Fischer, MD, PhD ^b,^r,^s,^x,^y, Marina Cavazzana, MD, PhD ^a,^b,^c, Isabelle André-Schmutz, PhD ^a,^b,^c,^⁎
^a Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France
^b Paris Descartes–Sorbonne Paris Cité University, Imagine Institute, Paris, France
^c Biotherapy Clinical Investigation Center, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
^e Laboratory of Oncohematology, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
^r French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
^s Pediatric Immunology Haematology and Rheumatology Unit, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
^d McGill University and Genome Québec Innovation Centre, Montreal, Quebec, Canada
^f Study Center for Primary Immunodeficiencies, Hôpital Necker Enfants-Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
^g Institut Curie, Centre de Recherche, Pavillon Pasteur, Paris, France
^h Institut National de la Santé et de la Recherche Médicale, Unité 932, Immunité et Cancer, Paris, France
ⁱ CIRI, International Center for Infectiology Research, EVIR group, INSERM U1111, CNRS, Université de Lyon-1, Lyon, France
^j INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), équipe “contrôle métabolique des morts cellulaires,” Nice, France
^k Laboratory of Immunogenetics of Pediatric Autoimmunity, INSERM UMR 1163, Necker Children's Hospital, Paris, France
^l Unité d'hémato-oncologie et greffes de moelle, CHU Rennes, CNRS UMR 6290, Université de Rennes 1, Rennes, France
^m Service d'Immunologie, Thérapie Cellulaire et Hématopoièse, CHU Rennes, Rennes, France
ⁿ Centre Hospitalier de Jolimont, La Louvière, Belgium
^o Hôpital Universitaire des enfants Reine Fabiola, Brussels, Belgium
^p Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
^q Departments of Internal Medicine and Immunology, Erasmus Medical Center, Rotterdam, The Netherlands
^t Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
^u Service de Pédiatrie, CHU Nord, Saint-Étienne, France
^v Department of Pediatrics, McGill University, McGill University Health Center, Montreal, Quebec, Canada
^w INSERM Unité U1163, Normal and Pathological Homeostasis of the Immune System, Hôpital Necker Enfants-Malades, Paris, France
^x INSERM Unité U1163, Hôpital Necker Enfants-Malades, Paris, France
^y Collège de France, Paris, France

^∗Corresponding author: Isabelle André-Schmutz, PhD, INSERM U1163, Institut Imagine, 24 Boulevard du Montparnasse, F-75015 Paris, France.INSERM U1163, Institut Imagine24 Boulevard du MontparnasseF-75015 ParisFrance

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.

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Key words : Leukopenia, primary immunodeficiency, moesin, ezrin-radixin-moesin protein, adhesion, migration

Abbreviations used : 7AAD, BCR, CFSE, ERM, FERM, G-CSF, IS, LFA-1, PB, PBS, SDF1a, TCR, VZV

Plan

Methods

Patient samples and cell preparations

Mutation detection and X-chromosome inactivation assays

Protein blotting

Transduction of human PBMCs

Analysis of the IS

Cell adhesion and migration assays

Results

Patients' clinical features

Identification of mutations in the MSN gene

MSN mutations are associated with altered MSN protein expression

Impaired proliferation after T-cell activation

The ^p.R171WMSN mutation has no effect on the IS

Impaired cell migration and adhesion in MSN-mutated T cells

Discussion

This research has received state funding from the French National Institute of Health and Medical Research (INSERM), the French National Research Agency (as part of the “Investments for the Future” program, reference: ANR-01-A0-IAHU), and the European Research Council (reference: PIDIMMUN 249816). A.B. was funded by La Ligue contre le Cancer and La Fondation ARC pour la Recherche sur le Cancer (DOC20120604712).

Disclosure of potential conflict of interest: C. Hivroz is employed by INSERM and has received grants from ANR, INSERM, and Institut Curie. The rest of the authors declare that they have no relevant conflicts of interest.

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Vol 138 - N° 6

P. 1681 - décembre 2016 Retour au numéro

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X-linked primary immunodeficiency associated with hemizygous mutations in the moesin (MSN) gene - 18/04/17

Abstract

Background

Objective

Methods

Results

Conclusion

Plan

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