Inherited human ezrin deficiency impairs adaptive immunity

作者：Blanca García‐Solis, Ana Van Den Rym, Laura Martínez‐Martínez, Teresa Franco-Leyva, Jareb J. Pérez-Caraballo, Janet Markle, Carolina Cubillos‐Zapata, Ana V. Marín, María J. Recio, José R. Regueiro, Alfonso Navarro‐Zapata, Carmen Mestre‐Durán, Cristina Ferreras, Carla Martín Cotázar, Rocío Mena, Carlos de la Calle‐Fabregat, Alberto López‐Lera, Miguel Fernández‐Arquero, Antonio Pérez‐Martínez, Eduardo López‐Collazo, Silvia Sánchez‐Ramón, Jean‐Laurent Casanova, Rubén Martínez‐Barricarte, Oscar De La Calle-Martin, Rebeca Pérez de Diego · 发表于：Journal of Allergy and Clinical Immunology · 年份：2023 · DOI：10.1016/j.jaci.2023.05.022 · 被引用次数：13 · 研究领域：Neurofibromatosis and Schwannoma Cases、Peripheral Neuropathies and Disorders、Hereditary Neurological Disorders

Background 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 central naive CD4 + cells. Conclusions Autosomal-recessive human ezrin deficiency is a newly recognized genetic cause of B-cell deficiency affecting cellular and humoral immunity.