Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 138, Issue 6, Pages 1681-+Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2016.04.032
Keywords
Leukopenia; primary immunodeficiency; moesin; ezrinradixin-moesin protein; adhesion; migration
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Funding
- French National Institute of Health and Medical Research (INSERM)
- French National Research Agency (Investments for the Future'' program) [ANR-01-A0-IAHU]
- European Research Council [PIDIMMUN 249816]
- La Ligue contre le Cancer
- La Fondation ARC pour la Recherche sur le Cancer [DOC20120604712]
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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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