XMEN disease reveals novel regulatory roles for magnesium in the immune system
The etiologies of human primary immunodeficiencies (PIDs) often yield novel insights about the immune system. This thesis revealed an unexpected regulatory role for magnesium in the immune system from the characterization of a novel PID now named X-linked immunodeficiency with magnesium defect, Epstein Barr Virus (EBV) infection and neoplasia (XMEN) disease. This story stemmed from the characterization of two young brothers of a non-consanguineous family exhibiting recurrent viral infections and decreased thymic output of CD4+ T cells. The mother of these two boys was found to have completely skewed lyonization in her T cells, suggesting that she carried a defective X-linked gene that confers decreased fitness relative to the wildtype allele. Using X-chromosome exon capture next-generation sequencing, a 10 base pair deletion ablating a splicing junction of Magnesium Transporter 1 (MAGT1) was found by identifying genes with missing coverage in the two boys but not in the mother. This mutation led to altered splicing, frameshift, early termination, and absent protein expression. Five additional unrelated patients with deleterious mutations in MAGT1 were later identified, and they all suffered from chronic EBV infections and a propensity to develop lymphomas. MagT1 is a magnesium selective transporter required for zebrafish development that had unknown roles in human biology. We found that MagT1 mediates a transient magnesium flux required for the function of inducible T cell kinase (ITK) upon T cell antigen receptor (TCR) stimulation, implicating Mg2+ as a novel second messenger. Moreover, we also found that MagT1 deficiency leads to decreased basal free Mg2+ and downmodulation of NKG2D, a receptor mediating antiviral and antitumor cytotoxicity, and both of these defects can be restored by magnesium supplementation. These findings not only explain the disease manifestation of XMEN patients but also provide diagnostic and/or therapeutic insights for this disease and disorders requiring immunomodulation such as autoimmunity and allograft rejections.