Signaling role for Mg(2+) revealed by immunodeficiency due to loss of MagT1

The magnesium ion, Mg(2+), is essential for all life as a cofactor for ATP, polyphosphates such as DNA and RNA, and metabolic enzymes, but whether it plays a role in intracellular signaling similar to Ca(2+) is unknown. In this study, 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 Mg(2+) influx is induced by antigen receptor stimulation in T cells or growth factor stimulation in non-lymphoid cells. MagT1 deficiency abrogates the Mg(2+) influx leading to impaired responses to antigen receptor engagement including defective activation of phospholipase Cγ and a markedly impaired Ca(2+) influx in T cells but not B cells. These observations reveal a role for Mg(2+) as an intracellular second messenger and identify MagT1 as a possible target for novel therapeutics.