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

Publication date: Available online 4 June 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): 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
BackgroundWe investigated seven male patients (from five different families) presenting with profound lymphopenia, hypogammaglobulinemia fluctuating monocytopenia and neutropenia,a poor immune response towards vaccine antigens and increased susceptibility to bacterial and varicella-zoster-virus infections,.ObjectiveTo characterize the genetic defect involved in a new form of X-linked immunodeficiency.MethodsGenetic analyses and an exhaustive phenotypic and functional characterization of the lymphocyte compartment.ResultsWe observed hemyzygous mutations in the MSN gene (located on the X chromosome and coding for moesin) in all seven patients. Six of the latter had the same missense mutation, which led to an amino acid substitution (R171W) in moesin's "four-point-one, ezrin, radixin, moesin" domain. The seventh patient had a nonsense mutation leading to a premature stop codon mutation (R533X). The naïve 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 moesin. Moesin-deficient T-cells also displayed poor chemokine receptor expression, elevated adhesion molecule expression and altered migration and adhesion capacities.DiscussionOur 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" (X-MAID).

Teaser

Defective expression of the protein moesin is associated with sustained leukopenia and low naïve T and B cell counts. Cell survival, migration and adhesion were particularly altered in T lymphocytes.


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