An Update on XMEN Disease

Abstract

"X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia" (XMEN) disease is an inborn error of glycosylation and immunity caused by loss of function mutations in the magnesium transporter 1 (MAGT1) gene. It is a multisystem disease that strongly affects certain immune cells. MAGT1 is now confirmed as a non-catalytic subunit of the oligosaccharyltransferase complex and facilitates Asparagine (N)-linked glycosylation of specific substrates, making XMEN a congenital disorder of glycosylation manifesting as a combined immune deficiency. The clinical disease has variable expressivity, and impaired glycosylation of key MAGT1-dependent glycoproteins in addition to Mg²⁺ abnormalities can explain some of the immune manifestations. NKG2D, an activating receptor critical for cytotoxic function against EBV, is poorly glycosylated and invariably decreased on CD8⁺ T cells and natural killer (NK) cells from XMEN patients. It is the best biomarker of the disease. The characterization of EBV-naïve XMEN patients has clarified features of the genetic disease that were previously attributed to EBV infection. Extra-immune manifestations, including hepatic and neurological abnormalities, have recently been reported. EBV-associated lymphomas remain the main cause of severe morbidity. Unfortunately, treatment options to address the underlying mechanism of disease remain limited and Mg²⁺ supplementation has not proven successful. Here, we review the expanding clinical phenotype and recent advances in glycobiology that have increased our understanding of XMEN disease. We also propose updating XMEN to "X-linked MAGT1 deficiency with increased susceptibility to EBV-infection and N-linked glycosylation defect" in light of these novel findings.

Keywords: CD28; CD70; Epstein-Barr virus; Immunodeficiency; MAGT1; NKG2D; XMEN disease; carbohydrate deficient transferrin; congenital disorders of glycosylation; lymphoma; magnesium; oligosaccharyltransferase complex.

Figure 1:. MAGT1 is a facilitator of N-linked glycosylation.

A dolichol-linked glycan precursor is assembled from monosaccharides units and en block transferred to proteins in the endoplasmic reticulum (ER) by either STT3A or STT3B, which are the catalytic subunits of the oligosaccharyltransferase (OST) complex. Either MAGT1 or TUSC3 associate with the STT3B-containing OST complex. Other accessory subunits common to both STT3A- and STT3B-OST complexes are not shown for simplicity. STT3A and STT3B catalyze the transfer of the pre-assembled glycans co-translationally and post-translationally, respectively. The transferred glycan is then further processed and modified in the ER and Golgi apparatus.

Figure 2:. Defective glycosylation of key immune molecules and pathogenesis of XMEN disease.

Immune cells, including CD8⁺ T lymphocytes, do not express TUSC3 and rely exclusively on MAGT1 to facilitate the N-linked glycosylation of some specific STT3B-substrates. Loss of MAGT1 in XMEN lymphocytes results in underglycosylation of key immune molecules, including NKG2D, CD28, CD70, and the T-cell receptor (TCR). In healthy individuals, these fully glycosylated proteins are normally expressed. In XMEN disease, decreased glycosylation of some molecules leads to their degradation resulting in their loss or decreased surface expression as is the case for NKG2D, CD28, and CD70. Other glycoproteins, such as the TCR, although hypoglycosylated in XMEN disease, are still expressed on the cell surface. Loss of NKG2D and CD70 expression impairs the cytotoxic activity of lymphocytes against EBV-infected B cells and result in increased risk of EBV-associated lymphoproliferation and lymphoma in XMEN disease.

Figure 3:. Clinical and laboratory findings in XMEN disease.

The percentage of all XMEN patients who presented with the given clinical manifestations (A) and laboratory findings (B). For clinical manifestations, the percentage of all reported patients with each phenotype is given. For the laboratory findings, only the percentage of patients who have had testing reported are shown. The number of patients reported with each symptom out of the number of patients tested is given for each. Bars are color coded for the prevalence of that finding in XMEN disease; red is 80–100 %, orange is 60–79 %, yellow is 40–59 %, green is 20–39 %, and blue is ≤ 19 %.