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 Hôpital 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 CIRI-EVIR - Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy [CIRI]
9 Equipe Inserm U1163 - Immunogenetics of pediatric autoimmune diseases
10 IGDR - Institut de Génétique et Développement de Rennes
11 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Pontchaillou]
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 ST-E - Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne]
20 the Genome Quebec Innovation Centre
21 Collège de France - Chaire Médecine expérimentale (A. Fischer)
2 Département de Biothérapie [CHU Necker]
3 McGill University and Genome Quebec Innovation Centre
4 Hôpital 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 CIRI-EVIR - Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy [CIRI]
9 Equipe Inserm U1163 - Immunogenetics of pediatric autoimmune diseases
10 IGDR - Institut de Génétique et Développement de Rennes
11 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Pontchaillou]
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 ST-E - Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne]
20 the Genome Quebec Innovation Centre
21 Collège de France - Chaire Médecine expérimentale (A. Fischer)
Els Verhoeyen
- Fonction : Auteur
- PersonId : 1100507
- ORCID : 0000-0001-9224-5491
- IdRef : 159656028
Cosset François-Loïc
- Fonction : Auteur
- PersonId : 746240
- IdHAL : francois-loic-cosset
- ORCID : 0000-0001-8842-3726
- IdRef : 11115104X
Capucine Picard
- Fonction : Auteur
- PersonId : 758297
- ORCID : 0000-0001-8788-5056
- IdRef : 091572363
Sven Kracker
- Fonction : Auteur
- PersonId : 738758
- IdHAL : sven-kracker
- ORCID : 0000-0003-4543-8236
- IdRef : 234576391
Claire Hivroz
- Fonction : Auteur
- PersonId : 839010
- ORCID : 0000-0002-6794-2890
- IdRef : 080637965
Nada Jabado
- Fonction : Auteur
- PersonId : 756555
- ORCID : 0000-0003-2485-3692
Marina Cavazzana
- Fonction : Auteur
- PersonId : 776350
- ORCID : 0000-0002-0264-0891
- IdRef : 084138653
Isabelle André-Schmutz
- Fonction : Auteur
- PersonId : 745689
- IdHAL : isabelleandreinsermfr
- ORCID : 0000-0002-3905-9910
- IdRef : 166097101
Résumé
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.