A new genetic cause of immunodeficiency has been discovered

Researchers from the Inflammatory Diseases group at the Sant Pau Research Institute (IR Sant Pau) participated in a multicenter study that has identified a new primary immunodeficiency or innate error of immunity. Primary immunodeficiencies are a group of over 500 genetic diseases that cause quantitative or functional defects in different components of the immune system, increasing susceptibility to infections, autoimmunity, and cancer. Specifically, this new disease causes a deficiency of B cells and alters the architecture of the immune system, affecting both cellular and humoral immunity.

This week, between April 22nd and 29th, marks the World Primary Immunodeficiency Week, an opportunity to raise awareness about this group of rare diseases that affect more than 1 million people worldwide.

Experts from various research centers in Spain, such as the IdiPAZ Health Research Institute at La Paz University Hospital, members of the Interdepartmental Group of Immunodeficiencies of Madrid, and the Biomedical Research Networking Center for Rare Diseases (CIBERER), as well as a group from the United States, participated in the study.

The study details the case of a patient with a primary immunodeficiency of unknown genetic origin. Through complete exome sequencing, researchers identified a homozygous mutation in the EZR gene, which encodes the protein known as ezrin. This mutation, called A129T, involves the substitution of the amino acid threonine with alanine at position 129.

Ezrin and its impact on the immune system

Ezrin is a protein associated with F-actin and is part of the ERM complex along with radixin and moesin. This complex acts as a link between the plasma membrane and the cytoskeleton, playing a crucial role in an efficient immune response, but with a significant role in many other cell types and tissues. The A129T mutation discovered in the patient impedes basal ezrin phosphorylation and decreases intracellular calcium signaling, causing a disruption of its function. Therefore, the presence of this mutation impacts multiple agents of the immune system and compromises its ability to defend the body against infections and diseases.

Dr. Oscar de la Calle, from the Inflammatory Diseases group at IR Sant Pau and principal investigator of the study, points out that “our results indicate that autosomal recessive ezrin deficiency in humans is a newly recognized genetic cause of lymphocyte deficiency affecting both cellular and humoral immunity. These new findings provide new perspectives for understanding and addressing immunological deficiencies, but also illustrate the difficulties in vaccine response in oncology patients after immunomodulatory treatments and after hematopoietic progenitor transplantation.”

This expert highlights the importance of studying patients with immunodeficiency to better understand both these rare diseases and the much more common situations of immunofragility. Furthermore, he explains that during the COVID-19 pandemic, the vulnerability of certain populations, such as the elderly, pregnant women, and chronic patients, particularly oncology patients, became apparent. These individuals share the presence of a more vulnerable immune system.

“Primary immunodeficiencies are well-established diseases, with very clear diagnostic criteria. Most have a known genetic cause. In fact, mutations in over 500 genes are currently described, with the particularity that many are among the few currently curable genetic diseases. To give us an idea of the scale, they are responsible for one in every 13 or 14 liver diseases. But we know that from the age of 50 or 60, there is a process called immunosenescence, which is the decrease in immune response that occurs during aging. Research into mutations that cause primary immunodeficiency helps us improve the diagnosis and treatment of fragile patients and also better understand the mechanisms behind the physiological process of senescence,” explains Dr. de la Calle.

Reference article

Blanca García-Solís, Ana Van Den Rym, Laura Martínez-Martínez, Teresa Franco, 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-Martín, Rebeca Pérez de Diego. Inherited human ezrin deficiency impairs adaptive immunity, Journal of Allergy and Clinical Immunology, Volume 152, Issue 4, 2023, Pages 997-1009.e11, ISSN 0091-6749,

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