García-Solís, Blanca et al.Rebeca Pérez de DiegoMartínez Martínez, Laura MaríaRecio Hoyas, María JoséFernández Arquero, MiguelSánchez Ramón, Silvia María2024-01-112024-01-112023-10García-Solís B, Van Den Rym A, Martinez-Martínez L, Franco T, Pérez-Caraballo JJ, Markle J, Cubillos-Zapata C, Marín AV, Recio MJ, Regueiro JR, Navarro-Zapata A, Mestre-Durán C, Ferreras C, Martín Cotázar C, Mena R, de la Calle-Fabregat C, López-Lera A, Fernández Arquero M, Pérez-Martínez A, López-Collazo E, Sánchez-Ramón S, Casanova JL, Martínez-Barricarte R, de la Calle-Martín O, Pérez de Diego R. J Allergy Clin Immunol. 2023 Oct;152(4):997-10090091-674910.1016/j.jaci.2023.05.022https://hdl.handle.net/20.500.14352/92656Background Inborn errors of immunity (IEI) are a group of monogenic diseases that confer susceptibility to infection, autoimmunity, and cancer. Despite the life-threatening consequences of some IEI, their genetic cause remains unknown in many patients. Objective We investigated a patient with an IEI of unknown genetic etiology. Methods Whole-exome sequencing identified a homozygous missense mutation of the gene encoding ezrin (EZR), substituting a threonine for an alanine at position 129. Results Ezrin is one of the subunits of the ezrin, radixin, and moesin (ERM) complex. The ERM complex links the plasma membrane to the cytoskeleton and is crucial for the assembly of an efficient immune response. The A129T mutation abolishes basal phosphorylation and decreases calcium signaling, leading to complete loss of function. Consistent with the pleiotropic function of ezrin in myriad immune cells, multidimensional immunophenotyping by mass and flow cytometry revealed that in addition to hypogammaglobulinemia, the patient had low frequencies of switched memory B cells, CD4+ and CD8+ T cells, MAIT, γδ T cells, and centralnaive CD4+ cells. Conclusions Autosomal-recessive human ezrin deficiency is a newly recognized genetic cause of B-cell deficiency affecting cellular and humoral immunity.engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/journal articlehttps://www.jacionline.org/article/S0091-6749(23)00749-2/fulltextopen access612.017EZRPrimary immunodeficiencyAntibody deficiencyComputational immunologyInborn errors of immunityLymphoid cellsMass cytometryNext-generation sequencingInmunología2412 Inmunología