DeCure for X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia
DeCure's autonomous Immuno AI scientist is researching a drug-repurposing hypothesis for X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleX-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for x-linked immunodeficiency with magnesium defect, epstein-barr virus infection and neoplasia is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
magnesium transporter 1 (MAGT1) — MAGT1 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet 4r,7rdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6S7T · 3.5 Å · ligand (4R,7R)-4-hydroxy-N,N,N-trimethyl-4,9-dioxo-7-[(undecanoyloxy)methyl]-3,5,8-trioxa-4lambda~5~-phosphadocosan-1-aminium (EGY). Experimental structure, not a prediction.
What the evidence adds up to
XMEN disease is caused by loss-of-function mutations in the gene encoding magnesium transporter 1 (MAGT1). The condition is X-linked recessive with complete penetrance but variable expressivity, and is characterised by chronic high-level Epstein-Barr virus (EBV) infection with increased numbers of EBV-infected B cells, immunodeficiency, immunodysregulation, and heightened susceptibility to EBV-associated lymphomas. Extraimmune manifestations including hepatic and neurological abnormalities have been reported in some patient cohorts. The disease was first characterised in 2014, and the genetic aetiology revealed an unexpected quantitative role for intracellular free magnesium in immune function. MAGT1 also acts as an accessory protein for STT3B, a catalytic subunit of the oligosaccharyltransferase complex that carries out N-glycosylation; glycans are essential for the stability, maturation and localisation of glycoproteins important in immune cell function.
A 2022 case report described a young man in Hong Kong managed as common variable immunodeficiency disease (CVID) since childhood, presenting with recurrent infection, hypogammaglobulinaemia, and immune thrombocytopenia (ITP). More than a decade after initial presentation, gene panel testing revealed a novel MAGT1 mutation, confirming XMEN disease. The authors noted that before next-generation sequencing (NGS), traditional workup relied heavily on phenotype studies followed by single-gene sequencing, with low diagnostic yield and significant delay in diagnosis. A 2021 case report described an 8-year-old Chinese boy with recurrent infections from birth who presented with a painless mass on his upper lip; excisional biopsy revealed EBV-positive extra-nodal marginal zone lymphoma (EBV+ EMZL). NGS identified a novel germline MAGT1 mutation (c.828_829insAT) predicted to cause premature truncation of MAGT1 (p.A277M.fs*11), inherited from his asymptomatic heterozygous carrier mother. This was the first known case of EBV+ EMZL associated with XMEN disease.
No controlled treatment trials for XMEN disease are reported in these abstracts. The 2014 review mentioned that the genetic discovery had led to novel diagnostic and therapeutic strategies, but gave no specific drug names, response rates, or survival data. The case reports describe diagnosis only, not treatment outcomes. The 2022 paper emphasised that the presentation varies among patients and overlaps with other clinical entities, making diagnosis challenging even with NGS.
What is still missing are prospective clinical trials testing any intervention, whether magnesium supplementation, antiviral agents, or targeted therapies. There are no data on optimal monitoring for lymphoma development, no validated biomarkers for disease activity, and no consensus on when to initiate treatment in asymptomatic individuals. Patient stratification by mutation type, residual MAGT1 function, and EBV viral load has not been attempted in a controlled setting. Funding for natural history studies and multi-centre registries would be needed before any drug can be evaluated.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Blood · 2014 · 184 citations
XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus
AbstractEpstein-Barr virus (EBV) is an oncogenic gammaherpesvirus that infects and persists in 95% of adults worldwide and has the potential to cause fatal disease, especially lymphoma, in immunocompromised hosts. Primary immunodeficiencies (PIDs) that predispose to EBV-associated malignancies have provided novel insights into the molecular mechanisms of immune defense against EBV. We have recently characterized a novel PID now named "X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia" (XMEN) disease characterized by loss-of-function mutations in the gene encoding magnesium transporter 1 (MAGT1), chronic high-level EBV with increased EBV-infected B cells, and heightened susceptibility to EBV-associated lymphomas. The genetic etiology of XMEN disease has revealed an unexpected quantitative role for intracellular free magnesium in immune functions and has led to novel diagnostic and therapeutic strategies. Here, we review the clinical presentation, genetic mutation spectrum, molecular mechanisms of pathogenesis, and diagnostic and therapeutic considerations for this previously unrecognized disease.
Case Reports in Immunology · 2022 · 5 citations · open access
Novel MAGT1 Mutation Found in the First Chinese XMEN in Hong Kong
AbstractThe availability of next-generation sequencing (NGS) helps to resolve many of the diagnostic odysseys. Common variable immunodeficiency disease (CVID) is an entity encompassing a heterogenous group of conditions with hypogammaglobulinemia, and it is a diagnosis of exclusion. In recent years, with the advances of molecular diagnostics, more and more patients have been reclassified with more defined entities after their genetic causes were found. Here, we reported a young man, who was managed as CVID since childhood, presenting with recurrent infection, hypogammaglobulinemia, and immune thrombocytopenia (ITP). Finally, more than a decade after initial presentation, gene panel testing revealed a novel mutation in the MAGT1 gene. Collectively, the genetic findings and clinical presentations confirm the diagnosis of X-linked immunodeficiency with magnesium defect and Epstein-Barr virus infection and neoplasia (XMEN). MAGT1 is an evolutionarily conserved, magnesium-specific transporter expressed in all mammalian cells that plays an essential role in magnesium homeostasis. MAGT1 also acts as an accessory protein for STT3B, as catalytic subunits of the oligosaccharyltransferase protein complex, which carries out glycan chain transfer to proteins in the endoplasmic reticulum during N-glycosylation. Glycans play an essential role in the stability, maturation, and localization in glycoproteins that are important in our immune cells' function. Mutation of the gene resulted in a rare X-linked recessive condition XMEN. The disease has complete penetrance but variable expressivity. It is mainly associated with immunodeficiency, immunodysregulation, and predisposition to EBV-associated lymphoproliferation. Extraimmune manifestations have also been reported in some patient cohorts, including hepatic and neurological abnormalities. Overall, the presentation varies among patients and overlaps with other clinical entities, in which diagnosis is challenging. Before the era of NGS, traditional workup hinges heavily on phenotype studies, followed by single-gene sequencing. The diagnostic yield is low, and a significant delay in diagnosis is common. This case illustrated the importance of early consideration of molecular studies in complex immunological cases without obvious secondary causes as an integral part of patient management.
Intracellular free Mg2+ is required to maintain NKG2D expression necessary for controlling EBV infection in XMEN disease (P3028)
AbstractAbstract Epstein-Barr virus (EBV) is a B cell-tropic gammaherpesvirus present in latent form in approximately 90% of people worldwide. However, a subset of immunocompromised hosts develop malignancy from uncontrolled EBV infection. While the etiology of such immunodeficiency states is sometimes apparent, as in HIV and post-transplant immunosuppression, the underlying immune deficiency is other cases remains unknown. X-linked immunodeficiency with Mg2+ defect, EBV infection, and neoplasia (XMEN) disease is a novel primary immunodeficiency characterized by deleterious mutations in magnesium transporter 1 (MAGT1), chronic EBV infection and increased susceptibility for EBV-associated lymphomas. We had previously demonstrated that MAGT1 mediates a second messenger role for Mg2+ during T cell activation. Here, we show that loss of MAGT1 also decreases the basal level of intracellular free Mg2+ and abolishes the expression of NKG2D on natural killer cells and cytotoxic T lymphocytes, leading to impaired cytotoxicity against EBV-transformed lymphoblastoid cell lines. Interestingly, both these defects can be restored in vitro and in vivo by exogenous Mg2+ supplementation, leading to decreased EBV-infected cells in vivo. This not only revealed the first specific molecular function of basal free Mg2+ in eukaryotic cells but also identified a novel Mg2+-dependent immune arm of defense against EBV lymphomagenesis that has profound diagnostic and therapeutic implications for XMEN disease.
Greater South Information System · 2021 · 0 citations · open access
Case Report: EBV-Positive Extra-Nodal Marginal Zone Lymphoma Associated With XMEN Disease Caused by a Novel Hemizygous Mutation in MAGT1
AbstractX-linked immunodeficiency with magnesium defect and Epstein-Barr virus infection and neoplasia (XMEN) disease is an X-linked genetic disorder of immune system caused by loss-of-function mutation in gene encoding Magnesium transporter 1 (MAGT1). Individuals with XMEN disease are prone to developing Epstein Barr Virus (EBV)-associated lymphomas. Herein, we report the first known case of an EBV+ EMZL associated with XMEN disease.The patient was an 8-year-old Chinese boy who suffered from recurrent infections from birth. Six months before, the patient presented with a painless mass on his upper lip and excisional biopsy revealed an EBV-positive extra-nodal marginal zone lymphoma (EBV+ EMZL). Furthermore, molecular investigations with next-generation sequencing identified a novel germline mutation in MAGT1 (c.828_829insAT) in the patient. The c.828_829insAT variant was predicted to cause premature truncation of MAGT1 (p.A277M.fs*11) and consequently was defined as likely pathogenic. The mutation was inherited from his asymptomatic heterozygous carrier mother. Hence the patient was diagnosed with an XMEN disease both clinically and genetically.Our results expand the genetic spectrum of XMEN disease and also the clinical spectrum of EBV+ EMZL. We highlight the importance of the genetic etiology underlying EBV+ lymphoma in the pediatric population.
Greater South Information System · 2021 · 0 citations · open access
Case Report: EBV-Positive Extra-Nodal Marginal Zone Lymphoma Associated With XMEN Disease Caused by a Novel Hemizygous Mutation in MAGT1
AbstractX-linked immunodeficiency with magnesium defect and Epstein-Barr virus infection and neoplasia (XMEN) disease is an X-linked genetic disorder of immune system caused by loss-of-function mutation in gene encoding Magnesium transporter 1 (MAGT1). Individuals with XMEN disease are prone to developing Epstein Barr Virus (EBV)-associated lymphomas. Herein, we report the first known case of an EBV+ EMZL associated with XMEN disease.The patient was an 8-year-old Chinese boy who suffered from recurrent infections from birth. Six months before, the patient presented with a painless mass on his upper lip and excisional biopsy revealed an EBV-positive extra-nodal marginal zone lymphoma (EBV+ EMZL). Furthermore, molecular investigations with next-generation sequencing identified a novel germline mutation in MAGT1 (c.828_829insAT) in the patient. The c.828_829insAT variant was predicted to cause premature truncation of MAGT1 (p.A277M.fs*11) and consequently was defined as likely pathogenic. The mutation was inherited from his asymptomatic heterozygous carrier mother. Hence the patient was diagnosed with an XMEN disease both clinically and genetically.Our results expand the genetic spectrum of XMEN disease and also the clinical spectrum of EBV+ EMZL. We highlight the importance of the genetic etiology underlying EBV+ lymphoma in the pediatric population.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
