Inherited human ezrin deficiency impairs adaptive immunity
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
Abstract
BackgroundInborn 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.ObjectiveWe investigated a patient with an IEI of unknown genetic etiology.MethodsWhole-exome sequencing identified a homozygous missense mutation of the gene encoding ezrin (EZR), substituting a threonine for an alanine at position 129.ResultsEzrin 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.ConclusionsAutosomal-recessive human ezrin deficiency is a newly recognized genetic cause of B-cell deficiency affecting cellular and humoral immunity. 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. We investigated a patient with an IEI of unknown genetic etiology. Whole-exome sequencing identified a homozygous missense mutation of the gene encoding ezrin (EZR), substituting a threonine for an alanine at position 129. 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. Autosomal-recessive human ezrin deficiency is a newly recognized genetic cause of B-cell deficiency affecting cellular and humoral immunity.