MAGT1 – X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia

XMEN disease is a primary immunodeficiency caused by hemizygous loss-of-function variants in the MAGT1 gene, characterized by chronic Epstein–Barr virus (EBV) infection, EBV-driven lymphomas, CD4 T-cell lymphopenia and dysgammaglobulinemia (PMID:25504528). Affected males frequently present in childhood or early adulthood with persistent EBV viremia, hypogammaglobulinemia and variable neoplastic complications. Intracellular Mg2+ homeostasis defects impair T-cell receptor signaling and natural killer cell cytotoxicity through loss of NKG2D expression, linking transporter dysfunction to immune failure. Recent reports extend the phenotype to include central nervous system vasculitis and variable responses to magnesium supplementation ([PMID:31865525], [PMID:34655400]).

Inheritance is X-linked recessive, with at least 14 unrelated hemizygous probands identified (7 original cases [PMID:25504528], 6 in 2020 [PMID:31865525], 1 novel in 2022 [PMID:35264785]) and documented maternal segregation in one family [PMID:35264785]. No affected female homozygotes have been reported. Segregation analyses support pathogenicity, and carrier mothers exhibit normal NKG2D expression on lymphocytes. Familial co-segregation of MAGT1 variants with clinical phenotypes reinforces the genetic association.

All reported causative alleles are predicted loss-of-function, including nonsense and frameshift variants. A recurrent example is c.616C>T (p.Arg206Ter), which truncates the transporter within the first transmembrane domain. Additional variants include c.1005T>A (p.Ser335Ter) and diverse null alleles (splice-site, frameshift) across exons. No missense variants with established pathogenicity have been consistently reported.

Functional studies provide concordant evidence that MAGT1 deficiency abrogates Mg2+ influx and disrupts N-linked glycosylation of key immune receptors. CRISPR/Cas9 MAGT1 knockout cell lines recapitulate hypoglycosylation defects and impaired CD28 signaling, and mRNA transfection restores receptor glycosylation and function ([PMID:31815737]). MS-based glycoproteomics in patient cells confirm selective loss of glycosylation on immune-response proteins, implicating both Mg2+ transport and OST3/OST6-like OST complex functions ([PMID:31337704]).

No studies have refuted the pathogenic link; however, randomized trials of magnesium supplementation failed to improve NKG2D expression or clinical outcomes ([PMID:34655400]). Epigenetic activation of the paralog TUSC3 rescues glycosylation defects in vitro, suggesting potential therapeutic strategies ([PMID:37086924]).

In summary, hemizygous loss-of-function MAGT1 variants cause X-linked susceptibility to EBV infection and lymphoproliferative disease through combined Mg2+ transporter and glycosylation defects. Genetic testing for MAGT1 should be prioritized in males with persistent EBV viremia and hypogammaglobulinemia. Key take-home: MAGT1 LOF testing enables definitive diagnosis and informs targeted research into glycosylation-based therapies.

References

• Journal of clinical immunology • 2015 • Identification of a novel mutation in MAGT1 and progressive multifocal leucoencephalopathy in a 58-year-old man with XMEN disease PMID:25504528
• Journal of clinical immunology • 2020 • Diversity of XMEN Disease: Description of 2 Novel Variants and Analysis of the Lymphocyte Phenotype PMID:31865525
• Genes and immunity • 2022 • Identification of a novel MAGT1 mutation supports a diagnosis of XMEN disease PMID:35264785
• The Journal of biological chemistry • 2019 • Magnesium transporter 1 (MAGT1) deficiency causes selective defects in N-linked glycosylation and expression of immune-response genes PMID:31337704
• The Journal of clinical investigation • 2020 • XMEN: welcome to the glycosphere PMID:31815737
• Journal of clinical immunology • 2022 • A Double-Blind, Placebo-Controlled, Crossover Study of Magnesium Supplementation in Patients with XMEN Disease PMID:34655400

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