X-linked primary immunodeficiency associated with hemizygous mutations in the moesin (MSN) gene.
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Lagresle-Peyrou Chantal, Luce Sonia, Ouchani Farid, Soheili Tayebeh Shabi, Sadek Hanem, Chouteau Myriam, Durand Amandine, Pic Isabelle, Majewski Jacek, Brouzes Chantal, Lambert Nathalie, Bohineust Armelle, Verhoeyen Els, Cosset François-Loïc, Magerus-Chatinet Aude, Rieux-Laucat Frédéric, Gandemer Virginie, Monnier Delphine, Heijmans Catherine, van Gijn Marielle, Dalm Virgil A, Mahlaoui Nizar, Stephan Jean-Louis, Picard Capucine, Durandy Anne, Kracker Sven, Hivroz Claire, Jabado Nada, de Saint Basile Geneviève, Fischer Alain, Cavazzana Marina, André-Schmutz Isabelle
Аннотация
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.