Effects of two different variants in the MAGT1 gene on B cell subsets, platelet function, and cell glycome composition
IntroductionX-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection and neoplasia (XMEN) disease is caused by hemizygous loss of function (LOF) gene variants in MAGT1. MAGT1 is a plasma membrane transporter of magnesium (Mg2+) that plays a relevant role in immune response...
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2025-03-01
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| author | Lucía del Pino Molina Elena Monzón Manzano Carla Gianelli Carla Gianelli Luz Yadira Bravo Gallego Luz Yadira Bravo Gallego Luz Yadira Bravo Gallego Javier Bujalance Fernández Paula Acuña Yolanda Soto Serrano Keren Reche Yebra María Bravo García-Morato María Bravo García-Morato María Bravo García-Morato Elena Sánchez Zapardiel Elena Sánchez Zapardiel Elena G. Arias-Salgado Rebeca Rodríguez Pena Rebeca Rodríguez Pena Rebeca Rodríguez Pena Nora Butta Eduardo López Granados Eduardo López Granados Eduardo López Granados |
| author_facet | Lucía del Pino Molina Elena Monzón Manzano Carla Gianelli Carla Gianelli Luz Yadira Bravo Gallego Luz Yadira Bravo Gallego Luz Yadira Bravo Gallego Javier Bujalance Fernández Paula Acuña Yolanda Soto Serrano Keren Reche Yebra María Bravo García-Morato María Bravo García-Morato María Bravo García-Morato Elena Sánchez Zapardiel Elena Sánchez Zapardiel Elena G. Arias-Salgado Rebeca Rodríguez Pena Rebeca Rodríguez Pena Rebeca Rodríguez Pena Nora Butta Eduardo López Granados Eduardo López Granados Eduardo López Granados |
| author_sort | Lucía del Pino Molina |
| collection | DOAJ |
| description | IntroductionX-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection and neoplasia (XMEN) disease is caused by hemizygous loss of function (LOF) gene variants in MAGT1. MAGT1 is a plasma membrane transporter of magnesium (Mg2+) that plays a relevant role in immune responses and acts as a second messenger in intracellular signaling, but also it is involved in the glycosylation of proteins. Here we report two gene variants in the MAGT1 gene from two different families with XMEN disease. A de novo variant c.97_98 delinsC affecting one member of one family and three members of a second family presented the hemizygous variant c.80``3G>A, p.Trp268Ter, causing a premature stop codon.MethodsWe performed a functional validation of these two variants in the MAGT1 gene and their association with decreased NKG2D expression, uncontrolled EBV viremia, and the development of lymphoma-associated complications in three members of the same family.ResultsWe analyzed the B-cell compartment, we found that the B-cell expansion is driven by immature/transitional (CD5- and CD5+) and naïve B cells. The patients presented normal absolute counts of memory B-cells (MBCs) but with differences between them in the diversity of immunoglobulin heavy chain (IgH) isotype distribution in MBC, and diverse reduction of plasma cells. We also explored the alterations of platelets due to hemorrhagic events and a history of thrombocytopenia in some of our patients. We found diminished TRAP-induced calcium flux, P-selectin and CD63 exposure in XMEN patients, while when platelets from patients were stimulated ADP the results were similar to healthy controls. Finally, we explored the glycosylation pattern in platelets and lymphocytes. Our results suggest that different variants in MAGT1 gene might result in different effects on NK cells and platelet glycome composition.DiscussionHere, we report the two different outcomes regarding EBV-driven lymphoproliferative complications, the family with three members affected that developed the malignant lymphoproliferative complications before XMEN diagnosis, and the patient with early diagnose of MAGT1 deficiency due to EBV viremia. As a recommendation, XMEN disease should be ruled out in males with impaired clearance of EBV-infection and EBV-driven lymphoproliferative complications. |
| format | Article |
| id | doaj-art-a259fb8f36c54b6fbabd038c28ec5d1b |
| institution | DOAJ |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-a259fb8f36c54b6fbabd038c28ec5d1b2025-08-20T03:13:36ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-03-011610.3389/fimmu.2025.15478081547808Effects of two different variants in the MAGT1 gene on B cell subsets, platelet function, and cell glycome compositionLucía del Pino Molina0Elena Monzón Manzano1Carla Gianelli2Carla Gianelli3Luz Yadira Bravo Gallego4Luz Yadira Bravo Gallego5Luz Yadira Bravo Gallego6Javier Bujalance Fernández7Paula Acuña8Yolanda Soto Serrano9Keren Reche Yebra10María Bravo García-Morato11María Bravo García-Morato12María Bravo García-Morato13Elena Sánchez Zapardiel14Elena Sánchez Zapardiel15Elena G. Arias-Salgado16Rebeca Rodríguez Pena17Rebeca Rodríguez Pena18Rebeca Rodríguez Pena19Nora Butta20Eduardo López Granados21Eduardo López Granados22Eduardo López Granados23Center for Biomedical Network Research on Rare Diseases (CIBERER U767), Madrid, SpainHematology Unit, La Paz University Hospital-IdiPAZ, Madrid, SpainLymphocyte Pathophysiology in Immunodeficiencies Group, La Paz Institute for Health Research (IdiPAZ), Madrid, SpainClinical Immunology Department, La Paz University Hospital, Madrid, SpainCenter for Biomedical Network Research on Rare Diseases (CIBERER U767), Madrid, SpainClinical Immunology Department, La Paz University Hospital, Madrid, SpainResearch on Comprehensive Care for Transplanted Children and Adolescent Group, La Paz Institute for Health Reserach (IdiPAZ), Madrid, SpainLymphocyte Pathophysiology in Immunodeficiencies Group, La Paz Institute for Health Research (IdiPAZ), Madrid, SpainHematology Unit, La Paz University Hospital-IdiPAZ, Madrid, SpainLymphocyte Pathophysiology in Immunodeficiencies Group, La Paz Institute for Health Research (IdiPAZ), Madrid, SpainLymphocyte Pathophysiology in Immunodeficiencies Group, La Paz Institute for Health Research (IdiPAZ), Madrid, SpainCenter for Biomedical Network Research on Rare Diseases (CIBERER U767), Madrid, SpainLymphocyte Pathophysiology in Immunodeficiencies Group, La Paz Institute for Health Research (IdiPAZ), Madrid, SpainClinical Immunology Department, La Paz University Hospital, Madrid, SpainLymphocyte Pathophysiology in Immunodeficiencies Group, La Paz Institute for Health Research (IdiPAZ), Madrid, SpainClinical Immunology Department, La Paz University Hospital, Madrid, SpainHematology Unit, La Paz University Hospital-IdiPAZ, Madrid, SpainCenter for Biomedical Network Research on Rare Diseases (CIBERER U767), Madrid, SpainLymphocyte Pathophysiology in Immunodeficiencies Group, La Paz Institute for Health Research (IdiPAZ), Madrid, SpainClinical Immunology Department, La Paz University Hospital, Madrid, SpainHematology Unit, La Paz University Hospital-IdiPAZ, Madrid, SpainCenter for Biomedical Network Research on Rare Diseases (CIBERER U767), Madrid, SpainLymphocyte Pathophysiology in Immunodeficiencies Group, La Paz Institute for Health Research (IdiPAZ), Madrid, SpainClinical Immunology Department, La Paz University Hospital, Madrid, SpainIntroductionX-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection and neoplasia (XMEN) disease is caused by hemizygous loss of function (LOF) gene variants in MAGT1. MAGT1 is a plasma membrane transporter of magnesium (Mg2+) that plays a relevant role in immune responses and acts as a second messenger in intracellular signaling, but also it is involved in the glycosylation of proteins. Here we report two gene variants in the MAGT1 gene from two different families with XMEN disease. A de novo variant c.97_98 delinsC affecting one member of one family and three members of a second family presented the hemizygous variant c.80``3G>A, p.Trp268Ter, causing a premature stop codon.MethodsWe performed a functional validation of these two variants in the MAGT1 gene and their association with decreased NKG2D expression, uncontrolled EBV viremia, and the development of lymphoma-associated complications in three members of the same family.ResultsWe analyzed the B-cell compartment, we found that the B-cell expansion is driven by immature/transitional (CD5- and CD5+) and naïve B cells. The patients presented normal absolute counts of memory B-cells (MBCs) but with differences between them in the diversity of immunoglobulin heavy chain (IgH) isotype distribution in MBC, and diverse reduction of plasma cells. We also explored the alterations of platelets due to hemorrhagic events and a history of thrombocytopenia in some of our patients. We found diminished TRAP-induced calcium flux, P-selectin and CD63 exposure in XMEN patients, while when platelets from patients were stimulated ADP the results were similar to healthy controls. Finally, we explored the glycosylation pattern in platelets and lymphocytes. Our results suggest that different variants in MAGT1 gene might result in different effects on NK cells and platelet glycome composition.DiscussionHere, we report the two different outcomes regarding EBV-driven lymphoproliferative complications, the family with three members affected that developed the malignant lymphoproliferative complications before XMEN diagnosis, and the patient with early diagnose of MAGT1 deficiency due to EBV viremia. As a recommendation, XMEN disease should be ruled out in males with impaired clearance of EBV-infection and EBV-driven lymphoproliferative complications.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1547808/fullXMENMAGT1plateletscalcium influxB cell phenotypeglycosylation |
| spellingShingle | Lucía del Pino Molina Elena Monzón Manzano Carla Gianelli Carla Gianelli Luz Yadira Bravo Gallego Luz Yadira Bravo Gallego Luz Yadira Bravo Gallego Javier Bujalance Fernández Paula Acuña Yolanda Soto Serrano Keren Reche Yebra María Bravo García-Morato María Bravo García-Morato María Bravo García-Morato Elena Sánchez Zapardiel Elena Sánchez Zapardiel Elena G. Arias-Salgado Rebeca Rodríguez Pena Rebeca Rodríguez Pena Rebeca Rodríguez Pena Nora Butta Eduardo López Granados Eduardo López Granados Eduardo López Granados Effects of two different variants in the MAGT1 gene on B cell subsets, platelet function, and cell glycome composition Frontiers in Immunology XMEN MAGT1 platelets calcium influx B cell phenotype glycosylation |
| title | Effects of two different variants in the MAGT1 gene on B cell subsets, platelet function, and cell glycome composition |
| title_full | Effects of two different variants in the MAGT1 gene on B cell subsets, platelet function, and cell glycome composition |
| title_fullStr | Effects of two different variants in the MAGT1 gene on B cell subsets, platelet function, and cell glycome composition |
| title_full_unstemmed | Effects of two different variants in the MAGT1 gene on B cell subsets, platelet function, and cell glycome composition |
| title_short | Effects of two different variants in the MAGT1 gene on B cell subsets, platelet function, and cell glycome composition |
| title_sort | effects of two different variants in the magt1 gene on b cell subsets platelet function and cell glycome composition |
| topic | XMEN MAGT1 platelets calcium influx B cell phenotype glycosylation |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1547808/full |
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