Abstract
The magnesium ion, Mg2+, is essential for all life as a cofactor for ATP, polyphosphates such as DNA and RNA, and metabolic enzymes, but whether it plays a part in intracellular signalling (as Ca2+ does) is unknown. Here we identify mutations in the magnesium transporter gene, MAGT1, in a novel X-linked human immunodeficiency characterized by CD4 lymphopenia, severe chronic viral infections, and defective T-lymphocyte activation. We demonstrate that a rapid transient Mg2+ influx is induced by antigen receptor stimulation in normal T cells and by growth factor stimulation in non-lymphoid cells. MAGT1 deficiency abrogates the Mg2+ influx, leading to impaired responses to antigen receptor engagement, including defective activation of phospholipase CĪ³1 and a markedly impaired Ca2+ influx in T cells but not B cells. These observations reveal a role for Mg2+ as an intracellular second messenger coupling cell-surface receptor activation to intracellular effectors and identify MAGT1 as a possible target for novel therapeutics.
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Data deposits
The Illumina sequencing data has been deposited in dbGaP with accession code phs000365.v1.p1.
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Acknowledgements
We thank L. Zheng, A. Weiss, R. Germain, R. Siegel, F. Wolf and P. Schwartzberg for critically reading the manuscript; F. Wolf for advice on magnesium assessments; L. Zheng, C. Lowell and A. Weiss for advice on experiments and data; H. Jing for making HVS lines from patient cells; P. Chen for assistance with plasmid DNA preparation; N. Sandler for flow cytometry assistance; A. Snow and H. Jing for assistance with genomic DNA library preparation for Solexa sequencing; J. Almenara and Illumina staff for Solexa assistance; D. Killilea for assistance with MS-ICP data interpretation; and A. Irani for referring the patients. F.-Y.L. is in the Medical Scientist Training Program at the University of CaliforniaāSan Francisco and thanks K. Shannon and J. Toutolmin for support and encouragement. This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health.
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F.-Y.L. characterized the MAGT1 mutations and the TCR activation defect in the patients. B.C.-D. characterized the Mg2+ influx and the signalling defects. B.C.-D., F.-Y.L., H.C.S. and M.J.L. conceived and planned the experiments, and prepared the manuscript. J.C.D. performed the lyonization assay. C.K. performed the RTāPCR experiments. G.U., J.I.C. and H.C.S. referred patients and provided clinical data. H.F.M. coordinated clinical protocol and sample collection. D.C.D. provided assistance with sequencing and flow cytometry, and guided some patient assessments. All authors discussed and revised the manuscript.
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This file contains Supplementary Table 1, Supplementary Figures 1-11 with legends, a Supplementary Discussion and additional references. (PDF 1726 kb)
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Li, FY., Chaigne-Delalande, B., Kanellopoulou, C. et al. Second messenger role for Mg2+ revealed by human T-cell immunodeficiency. Nature 475, 471ā476 (2011). https://doi.org/10.1038/nature10246
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DOI: https://doi.org/10.1038/nature10246
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