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Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease

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

  2. Author Address

    NIAID, Mol Dev Immune Syst Sect, Lab Immune Syst Biol, 9000 Rockville Pike, Bethesda, MD 20892 USA.NIAID, Clin Genom Program, Div Intramural Res, 9000 Rockville Pike, Bethesda, MD 20892 USA.Max Planck Inst Biogeochem, Prote & Signal Transduct Grp & Computat Syst Bioc, Martinsried, Germany.NIAID, Lab Clin Immunol & Microbiol, Div Intramural Res, 9000 Rockville Pike, Bethesda, MD 20892 USA.NINDS, Neuroimmunol Branch, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA.NCI, Ctr Canc Res, Bldg 37,Room 4134, Bethesda, MD 20892 USA.NIH, Trans NIH Ctr Human Immunol Autoimmun & Inflammat, Bldg 10, Bethesda, MD 20892 USA.Shenzhen Childrens Hosp, Dept Rheumatol & Immunol, Shenzhen, Guangdong, Peoples R China.NCI, Hematopathol Sect, Pathol Lab, Bethesda, MD 20892 USA.NCI, Pathol Lab, Bldg 10, Bethesda, MD 20892 USA.NIDDK, Liver Dis Branch, Bethesda, MD 20892 USA.NIAID, Biostat Res Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA.NIAID, Med Virol Sect, Infect Dis Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA.NHGRI, Bethesda, MD 20892 USA.NIH, Radiol & Imaging Sci, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA.NCI, Clin Monitoring Res Program Directorate, Frederick Natl Lab Canc Res, NIH, Bethesda, MD 20892 USA.Texas Childrens Hosp, Baylor Coll Med, Houston, TX 77030 USA.Univ Antioquia UdeA, Fac Med, Grp Inmunodeficiencias Primarias, Medellin, Colombia.Carolinas Med Ctr, Dept Pediat, Sect Infect Dis & Immunol, Charlotte, NC 28203 USA.Levine Childrens Hosp Atrium Hlth, Charlotte, NC USA.Mayo Clin, Biochem Genet Lab, Dept Lab Med & Pathol, Coll Med, Rochester, MN USA.Erciyes Univ, Fac Med, Dept Pediat, Kayseri, Turkey.Boston Univ, Dept Phys, 590 Commonwealth Ave, Boston, MA 02215 USA.Univ Tokushima, Inst Adv Med Sci, Div Expt Immunol, Tokushima, Japan.NYU, Langone Med Ctr, New York, NY USA.Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA.Columbia Univ, Vagelos Coll Phys & Surg, New York, NY USA.Univ Calif San Diego, Sch Med, San Diego, CA 92103 USA.
    1. Year: 2020
    2. Date: Jan
  2. Journal: JOURNAL OF CLINICAL INVESTIGATION
  3. AMER SOC CLINICAL INVESTIGATION INC,
    1. 130
    2. 1
    3. Pages: 507-522
  5. Type of Article: Article
  6. ISSN: 0021-9738
  1. 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-TCR alpha beta(+) T cells (alpha beta DNTs), 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. EBV-associated 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(+)HLA-DR(+)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.

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  2. DOI: 10.1172/JCI131116
  3. PMID: 31714901
  4. PMCID: PMC6934229
  5. View record in Web of Science®
  6. WOS: 000505205000048

Library Notes

  1. Fiscal Year: FY2019-2020
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