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2011 NIAID Year In Review

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Scientists Identify the Genetic Mutation Causing "XMEN" Disease

Primary immune deficiency diseases (PIDDs) are caused by inherited genetic mutations that affect one or more parts of the immune system. Though rare, these disorders are chronic, debilitating, and associated with severe microbial infections and cancers. The condition known as idiopathic CD4 lymphocytopenia (ICL)—in which patients have very low numbers of circulating white blood cells known as CD4 T cells—has long been suspected to be a PIDD. In addition to certain fungal and bacterial infections, some ICL patients develop chronic Epstein-Barr virus (EBV) infections, making them more susceptible to cancer.

Identifying the genetic mutation that causes ICL could lead to better treatments. In this study, NIAID investigators sought to identify the genetic factors leading to ICL in two young brothers and another unrelated male patient who all had persistent EBV infection.

After ruling out other possibilities, the study team proposed that the genetic defect may be present on the X chromosome. Using a technique that detects mutations in regions of genes that make proteins, the researchers detected a mutation in the magnesium transporter 1 (MAGT1) gene. Found on the X chromosome, this gene encodes a protein that moves magnesium into T cells. Without magnesium, the cells do not function properly.

Investigating this lead further, the team found that T cells from the three males indeed lacked the ability to take up magnesium easily and had limited activation compared to cells from healthy donors. This finding provides further evidence for the importance of magnesium for proper T-cell functioning and immunity to EBV. It also provided a more accurate diagnosis of X-linked magnesium deficiency with EBV infection and neoplasia (XMEN) for the patients. The results suggest that augmenting MAGT1 activity may be a possible therapy for people with ICL or XMEN.

Reference: Li FY, Chaigne-Delalande B, Kanellopoulou C, Davis JC, Matthews HF, Douek DC, Cohen JI, Uzel G, Su HC, Lenardo MJ. Second messenger role for Mg2+ revealed by human T-cell immunodeficiency. Nature. 2011 Jul 27;475(7357):471-6.

Last Updated January 07, 2013

Last Reviewed January 07, 2013