<p>The etiologies of primary immunodeficiencies often yield novel insights about the immune system. Although a genetic etiology has     been suspected for patients with abnormally low CD4+ T cells in the absence of HIV infection or any known causes of lymphopenia,     no genetic mutation has been described to date for any case of primary CD4 lymphopenia. In this study, we characterized a     non-consanguineous family with two non-HIV infected boys exhibiting an inverted CD4 to CD8 T cell ratio and a history of     recurrent chronic viral infections since birth. Consistent with a decreased thymic output of CD4+ T cells, the percentage     of CD31+ cells in the CD4+ naive population of these patients was decreased. In addition, the activation of T cells was     significantly impaired in the patient upon TCR stimulation. Given the mother's T cells show completely skewed X chromosome     inactivation, we suspected that the nature of this disease is X-linked. We performed X-chromosome exon-capture targeted     single-end Solexa sequencing on two brothers and the mother and found a 10 base pair deletion at an intron-exon junction     of Magnesium Transporter 1 (MAGT1), a Mg<sup>2+</sup> specific transporter. We confirmed that this deletion leads to altered splicing,     frameshift, early termination of the mRNA, and deficient protein expression in the lymphocytes of the two patients.     Moreover, knockdown of this transporter in T cells isolated from healthy donors can recapitulate the observed T cell     activation defect while its ectopic expression in the patients' lymphocytes can restore T cell stimulation. Our discovery     highlights the significance of this transporter to T cell function.</p>

Genetic Basis of XMEN Disease

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