Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease

Juan C. Ravell; Mami Matsuda-Lennikov; Samuel D. Chauvin; Juan Zou; Matthew Biancalana; Sally J. Deeb; Susan Price; Helen C. Su; Giulia Notarangelo; Ping Jiang; Aaron Morawski; Chrysi Kanellopoulou; Kyle Binder; Ratnadeep Mukherjee; James T. Anibal; Brian Sellers; Lixin Zheng; Tingyan He; Alex B. George; Stefania Pittaluga; Astin Powers; David E. Kleiner; Devika Kapuria; Marc Ghany; Sally Hunsberger; Jeffrey I. Cohen; Gulbu Uzel; Jenna Bergerson; Lynne Wolfe; Camilo Toro; William Gahl; Les R. Folio; Helen Matthews; Pam Angelus; Ivan K. Chinn; Jordan S. Orange; Claudia M. Trujillo-Vargas; Jose Luis Franco; Julio Orrego-Arango; Sebastian Gutiérrez-Hincapié; Niraj Chandrakant Patel; Kimiyo Raymond; Turkan Patiroglu; Ekrem Unal; Musa Karakukcu; Alexandre G.R. Day; Pankaj Mehta; Evan Masutani; Suk S. De Ravin; Harry L. Malech; Grégoire Altan-Bonnet; V. Koneti Rao; Matthias Mann; Michael J. Lenardo

doi:10.1172/JCI131116

Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease

Juan C. Ravell, Mami Matsuda-Lennikov, Samuel D. Chauvin, Juan Zou, Matthew Biancalana, Sally J. Deeb, Susan Price, Helen C. Su, Giulia Notarangelo, Ping Jiang, Aaron Morawski, Chrysi Kanellopoulou, Kyle Binder, Ratnadeep Mukherjee, James T. Anibal, Brian Sellers, Lixin Zheng, Tingyan He, Alex B. George, Stefania PittalugaAstin Powers, David E. Kleiner, Devika Kapuria, Marc Ghany, Sally Hunsberger, Jeffrey I. Cohen, Gulbu Uzel, Jenna Bergerson, Lynne Wolfe, Camilo Toro, William Gahl, Les R. Folio, Helen Matthews, Pam Angelus, Ivan K. Chinn, Jordan S. Orange, Claudia M. Trujillo-Vargas, Jose Luis Franco, Julio Orrego-Arango, Sebastian Gutiérrez-Hincapié, Niraj Chandrakant Patel, Kimiyo Raymond, Turkan Patiroglu, Ekrem Unal, Musa Karakukcu, Alexandre G.R. Day, Pankaj Mehta, Evan Masutani, Suk S. De Ravin, Harry L. Malech, Grégoire Altan-Bonnet, V. Koneti Rao, Matthias Mann, Michael J. Lenardo

Division of Gastroenterology

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54 Scopus citations

Abstract

X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) disease are caused by deficiency of the magnesium transporter 1 (MAGT1) gene. We studied 23 patients with XMEN, 8 of whom were EBV naive. We observed lymphadenopathy (LAD), cytopenias, liver disease, cavum septum pellucidum (CSP), and increased CD4-CD8-B220-TCRαβ+ T cells (αβDNTs), in addition to the previously described features of an inverted CD4/CD8 ratio, CD4+ T lymphocytopenia, increased B cells, dysgammaglobulinemia, and decreased expression of the natural killer group 2, member D (NKG2D) receptor. EBVassociated B cell malignancies occurred frequently in EBV-infected patients. We studied patients with XMEN and patients with autoimmune lymphoproliferative syndrome (ALPS) by deep immunophenotyping (32 immune markers) using time-of-flight mass cytometry (CyTOF). Our analysis revealed that the abundance of 2 populations of naive B cells (CD20+CD27-CD22+IgM+HLADR+ CXCR5+CXCR4++CD10+CD38+ and CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4+CD10-CD38-) could differentially classify XMEN, ALPS, and healthy individuals. We also performed glycoproteomics analysis on T lymphocytes and show that XMEN disease is a congenital disorder of glycosylation that affects a restricted subset of glycoproteins. Transfection of MAGT1 mRNA enabled us to rescue proteins with defective glycosylation. Together, these data provide new clinical and pathophysiological foundations with important ramifications for the diagnosis and treatment of XMEN disease.

Original language	English
Pages (from-to)	507-522
Number of pages	16
Journal	Journal of Clinical Investigation
Volume	130
Issue number	1
DOIs	https://doi.org/10.1172/JCI131116
State	Published - Jan 2 2020

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10.1172/JCI131116

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Ravell, J. C., Matsuda-Lennikov, M., Chauvin, S. D., Zou, J., Biancalana, M., Deeb, S. J., Price, S., Su, H. C., Notarangelo, G., Jiang, P., Morawski, A., Kanellopoulou, C., Binder, K., Mukherjee, R., Anibal, J. T., Sellers, B., Zheng, L., He, T., George, A. B., ... Lenardo, M. J. (2020). Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease. Journal of Clinical Investigation, 130(1), 507-522. https://doi.org/10.1172/JCI131116

@article{f3562468ff2949dfa4e519f1742c28f6,

title = "Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease",

abstract = "X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) disease are caused by deficiency of the magnesium transporter 1 (MAGT1) gene. We studied 23 patients with XMEN, 8 of whom were EBV naive. We observed lymphadenopathy (LAD), cytopenias, liver disease, cavum septum pellucidum (CSP), and increased CD4-CD8-B220-TCRαβ+ T cells (αβDNTs), in addition to the previously described features of an inverted CD4/CD8 ratio, CD4+ T lymphocytopenia, increased B cells, dysgammaglobulinemia, and decreased expression of the natural killer group 2, member D (NKG2D) receptor. EBVassociated B cell malignancies occurred frequently in EBV-infected patients. We studied patients with XMEN and patients with autoimmune lymphoproliferative syndrome (ALPS) by deep immunophenotyping (32 immune markers) using time-of-flight mass cytometry (CyTOF). Our analysis revealed that the abundance of 2 populations of naive B cells (CD20+CD27-CD22+IgM+HLADR+ CXCR5+CXCR4++CD10+CD38+ and CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4+CD10-CD38-) could differentially classify XMEN, ALPS, and healthy individuals. We also performed glycoproteomics analysis on T lymphocytes and show that XMEN disease is a congenital disorder of glycosylation that affects a restricted subset of glycoproteins. Transfection of MAGT1 mRNA enabled us to rescue proteins with defective glycosylation. Together, these data provide new clinical and pathophysiological foundations with important ramifications for the diagnosis and treatment of XMEN disease.",

author = "Ravell, {Juan C.} and Mami Matsuda-Lennikov and Chauvin, {Samuel D.} and Juan Zou and Matthew Biancalana and Deeb, {Sally J.} and Susan Price and Su, {Helen C.} and Giulia Notarangelo and Ping Jiang and Aaron Morawski and Chrysi Kanellopoulou and Kyle Binder and Ratnadeep Mukherjee and Anibal, {James T.} and Brian Sellers and Lixin Zheng and Tingyan He and George, {Alex B.} and Stefania Pittaluga and Astin Powers and Kleiner, {David E.} and Devika Kapuria and Marc Ghany and Sally Hunsberger and Cohen, {Jeffrey I.} and Gulbu Uzel and Jenna Bergerson and Lynne Wolfe and Camilo Toro and William Gahl and Folio, {Les R.} and Helen Matthews and Pam Angelus and Chinn, {Ivan K.} and Orange, {Jordan S.} and Trujillo-Vargas, {Claudia M.} and Franco, {Jose Luis} and Julio Orrego-Arango and Sebastian Guti{\'e}rrez-Hincapi{\'e} and Patel, {Niraj Chandrakant} and Kimiyo Raymond and Turkan Patiroglu and Ekrem Unal and Musa Karakukcu and Day, {Alexandre G.R.} and Pankaj Mehta and Evan Masutani and {De Ravin}, {Suk S.} and Malech, {Harry L.} and Gr{\'e}goire Altan-Bonnet and Rao, {V. Koneti} and Matthias Mann and Lenardo, {Michael J.}",

note = "Funding Information: This work was supported by the Division of Intramural Research, NIAID, NIH; the Intramural Research Program of the National Human Genome Research Institute, NIH; the Japan Society for the Promotion of Science (JSPS) and NIH grant (71403); and by cofunding through the Office of Disease Prevention, NIH. MML was supported by a Uehara Research Fellowship from the Uehara Memorial Foundation (201330032). We also acknowledge the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute for their grant (UM1 HG006542) to the Baylor-Hopkins Center for Mendelian Genomics; the NIAID for their grant (NIH R01-AI120989) to JSO; and COLCIENCIAS for their grant (1115.569.34430) to the Universidad de Antioquia. This project was also supported by federal funds from the NCI under contract HHSN261200800001E. The CyTOF Facility at the Center for Human Immunology is supported by NIH intramural funding (AI001226-01). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. The authors thank Ryan Kissinger for designing the diagrams, Brigit S. Sullivan for reviewing the manuscript, and Hudson H. Freeze for important insights and advice. We thank James R Lupski, Richard Gibbs, and Zeynep Coban-Akdemir for their contribution in the genetic diagnosis of one of our patients. We thank Maxcyte Inc. for providing the MAGT1 and GFP mRNAs and their collaboration. Finally, we thank all patients described in this manuscript and their families for facilitating this work. Publisher Copyright: {\textcopyright} 2020, American Society for Clinical Investigation.",

year = "2020",

month = jan,

day = "2",

doi = "10.1172/JCI131116",

language = "English",

volume = "130",

pages = "507--522",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

number = "1",

}

Ravell, JC, Matsuda-Lennikov, M, Chauvin, SD, Zou, J, Biancalana, M, Deeb, SJ, Price, S, Su, HC, Notarangelo, G, Jiang, P, Morawski, A, Kanellopoulou, C, Binder, K, Mukherjee, R, Anibal, JT, Sellers, B, Zheng, L, He, T, George, AB, Pittaluga, S, Powers, A, Kleiner, DE, Kapuria, D, Ghany, M, Hunsberger, S, Cohen, JI, Uzel, G, Bergerson, J, Wolfe, L, Toro, C, Gahl, W, Folio, LR, Matthews, H, Angelus, P, Chinn, IK, Orange, JS, Trujillo-Vargas, CM, Franco, JL, Orrego-Arango, J, Gutiérrez-Hincapié, S, Patel, NC, Raymond, K, Patiroglu, T, Unal, E, Karakukcu, M, Day, AGR, Mehta, P, Masutani, E, De Ravin, SS, Malech, HL, Altan-Bonnet, G, Rao, VK, Mann, M & Lenardo, MJ 2020, 'Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease', Journal of Clinical Investigation, vol. 130, no. 1, pp. 507-522. https://doi.org/10.1172/JCI131116

TY - JOUR

T1 - Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease

AU - Ravell, Juan C.

AU - Matsuda-Lennikov, Mami

AU - Chauvin, Samuel D.

AU - Zou, Juan

AU - Biancalana, Matthew

AU - Deeb, Sally J.

AU - Price, Susan

AU - Su, Helen C.

AU - Notarangelo, Giulia

AU - Jiang, Ping

AU - Morawski, Aaron

AU - Kanellopoulou, Chrysi

AU - Binder, Kyle

AU - Mukherjee, Ratnadeep

AU - Anibal, James T.

AU - Sellers, Brian

AU - Zheng, Lixin

AU - He, Tingyan

AU - George, Alex B.

AU - Pittaluga, Stefania

AU - Powers, Astin

AU - Kleiner, David E.

AU - Kapuria, Devika

AU - Ghany, Marc

AU - Hunsberger, Sally

AU - Cohen, Jeffrey I.

AU - Uzel, Gulbu

AU - Bergerson, Jenna

AU - Wolfe, Lynne

AU - Toro, Camilo

AU - Gahl, William

AU - Folio, Les R.

AU - Matthews, Helen

AU - Angelus, Pam

AU - Chinn, Ivan K.

AU - Orange, Jordan S.

AU - Trujillo-Vargas, Claudia M.

AU - Franco, Jose Luis

AU - Orrego-Arango, Julio

AU - Gutiérrez-Hincapié, Sebastian

AU - Patel, Niraj Chandrakant

AU - Raymond, Kimiyo

AU - Patiroglu, Turkan

AU - Unal, Ekrem

AU - Karakukcu, Musa

AU - Day, Alexandre G.R.

AU - Mehta, Pankaj

AU - Masutani, Evan

AU - De Ravin, Suk S.

AU - Malech, Harry L.

AU - Altan-Bonnet, Grégoire

AU - Rao, V. Koneti

AU - Mann, Matthias

AU - Lenardo, Michael J.

N1 - Funding Information: This work was supported by the Division of Intramural Research, NIAID, NIH; the Intramural Research Program of the National Human Genome Research Institute, NIH; the Japan Society for the Promotion of Science (JSPS) and NIH grant (71403); and by cofunding through the Office of Disease Prevention, NIH. MML was supported by a Uehara Research Fellowship from the Uehara Memorial Foundation (201330032). We also acknowledge the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute for their grant (UM1 HG006542) to the Baylor-Hopkins Center for Mendelian Genomics; the NIAID for their grant (NIH R01-AI120989) to JSO; and COLCIENCIAS for their grant (1115.569.34430) to the Universidad de Antioquia. This project was also supported by federal funds from the NCI under contract HHSN261200800001E. The CyTOF Facility at the Center for Human Immunology is supported by NIH intramural funding (AI001226-01). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. The authors thank Ryan Kissinger for designing the diagrams, Brigit S. Sullivan for reviewing the manuscript, and Hudson H. Freeze for important insights and advice. We thank James R Lupski, Richard Gibbs, and Zeynep Coban-Akdemir for their contribution in the genetic diagnosis of one of our patients. We thank Maxcyte Inc. for providing the MAGT1 and GFP mRNAs and their collaboration. Finally, we thank all patients described in this manuscript and their families for facilitating this work. Publisher Copyright: © 2020, American Society for Clinical Investigation.

PY - 2020/1/2

Y1 - 2020/1/2

N2 - X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) disease are caused by deficiency of the magnesium transporter 1 (MAGT1) gene. We studied 23 patients with XMEN, 8 of whom were EBV naive. We observed lymphadenopathy (LAD), cytopenias, liver disease, cavum septum pellucidum (CSP), and increased CD4-CD8-B220-TCRαβ+ T cells (αβDNTs), in addition to the previously described features of an inverted CD4/CD8 ratio, CD4+ T lymphocytopenia, increased B cells, dysgammaglobulinemia, and decreased expression of the natural killer group 2, member D (NKG2D) receptor. EBVassociated B cell malignancies occurred frequently in EBV-infected patients. We studied patients with XMEN and patients with autoimmune lymphoproliferative syndrome (ALPS) by deep immunophenotyping (32 immune markers) using time-of-flight mass cytometry (CyTOF). Our analysis revealed that the abundance of 2 populations of naive B cells (CD20+CD27-CD22+IgM+HLADR+ CXCR5+CXCR4++CD10+CD38+ and CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4+CD10-CD38-) could differentially classify XMEN, ALPS, and healthy individuals. We also performed glycoproteomics analysis on T lymphocytes and show that XMEN disease is a congenital disorder of glycosylation that affects a restricted subset of glycoproteins. Transfection of MAGT1 mRNA enabled us to rescue proteins with defective glycosylation. Together, these data provide new clinical and pathophysiological foundations with important ramifications for the diagnosis and treatment of XMEN disease.

AB - X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) disease are caused by deficiency of the magnesium transporter 1 (MAGT1) gene. We studied 23 patients with XMEN, 8 of whom were EBV naive. We observed lymphadenopathy (LAD), cytopenias, liver disease, cavum septum pellucidum (CSP), and increased CD4-CD8-B220-TCRαβ+ T cells (αβDNTs), in addition to the previously described features of an inverted CD4/CD8 ratio, CD4+ T lymphocytopenia, increased B cells, dysgammaglobulinemia, and decreased expression of the natural killer group 2, member D (NKG2D) receptor. EBVassociated B cell malignancies occurred frequently in EBV-infected patients. We studied patients with XMEN and patients with autoimmune lymphoproliferative syndrome (ALPS) by deep immunophenotyping (32 immune markers) using time-of-flight mass cytometry (CyTOF). Our analysis revealed that the abundance of 2 populations of naive B cells (CD20+CD27-CD22+IgM+HLADR+ CXCR5+CXCR4++CD10+CD38+ and CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4+CD10-CD38-) could differentially classify XMEN, ALPS, and healthy individuals. We also performed glycoproteomics analysis on T lymphocytes and show that XMEN disease is a congenital disorder of glycosylation that affects a restricted subset of glycoproteins. Transfection of MAGT1 mRNA enabled us to rescue proteins with defective glycosylation. Together, these data provide new clinical and pathophysiological foundations with important ramifications for the diagnosis and treatment of XMEN disease.

UR - http://www.scopus.com/inward/record.url?scp=85077401502&partnerID=8YFLogxK

U2 - 10.1172/JCI131116

DO - 10.1172/JCI131116

M3 - Article

C2 - 31714901

AN - SCOPUS:85077401502

SN - 0021-9738

VL - 130

SP - 507

EP - 522

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 1

ER -

Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease

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