“X-linked MAGT1缺乏症，具有易感EBV感染和N-连接糖基化缺陷（XMEN）疾病是一种罕见的综合免疫缺陷（CID），由于镁转运蛋白1（MAGT1）基因失活突变所致。MAGT1缺失影响镁转运和一些蛋白质的N-糖基化，进而取消关键免疫受体，如自然杀伤性2族D（NKG2D）的表达。这些影响导致免疫系统异常，慢性EBV感染和肿瘤。 最近的研究表明，MAGT1和肿瘤候选抑制因子3（TUSC3）具有高度的序列和功能相似性。我们试图研究激活TUSC3表达以提供XMEN疾病潜在治疗策略的可行性。使用多个数据库，RT-PCR和Western blot分析了MAGT1和TUSC3的表达谱。在MAGT1敲除（KO）/患者来源淋巴细胞和MAGT1 KO肝细胞中探索了脱氧表胞苷和帕诺比尼斯塔对TUSC3表达的调节作用。尽管TUSC3广泛表达，但在免疫系统和肝脏中特异性不可检测，与XMEN患者的主要患病组织一致。使用CRISPR / Cas9介导的MAGT1 KO NKL细胞系成功模拟了XMEN患者来源淋巴细胞的表型，并且TUSC3的外源性表达挽救了KO NKL细胞中的缺陷。使用这个体外模型，我们通过筛选确定了两种表观遗传药物，即脱氧表胞苷和帕诺比尼斯塔。使用这两种药物的联合治疗显著上调了TUSC3的表达，并挽救了免疫和肝功能异常。表观遗传激活TUSC3表达构成了XMEN疾病的有效治疗策略。” 版权所有©2023 Elsevier Inc.发布。

"X-linked MAGT1 deficiency with increased susceptibility to EBV infection and N-linked glycosylation defect" (XMEN) disease is a rare combined immunodeficiency (CID) caused by loss of function mutations in the magnesium transporter 1 (MAGT1) gene. MAGT1 deficiency impairs magnesium transport and the N-glycosylation of a panel of proteins, which subsequently abolishes the expression of key immune receptors such as Natural-Killer Group 2, member D (NKG2D). These effects induce immune system abnormalities, chronic EBV infection and neoplasia. Recent research shows that MAGT1 and tumor candidate suppressor 3 (TUSC3) share high sequence and functional similarity.We sought to investigate the feasibility of activating TUSC3 expression to provide a potential therapeutic strategy for XMEN disease.The expression profiles of MAGT1 and TUSC3 were analyzed using multiple databases, RT‒PCR, and western blot. The effects of decitabine and panobinostat on the regulation of TUSC3 expression were explored in both MAGT1 knock-out (KO)/patient-derived lymphocytes and MAGT1 KO hepatocytes.Although TUSC3 is widely expressed, it is undetectable specifically in the immune system and liver, consistent with the main diseased tissues in XMEN patients. CRISPR/Cas9-mediated KO of MAGT1 in the NKL cell line successfully mimicked the phenotypes of XMEN patient-derived lymphocytes, and exogenous expression of TUSC3 rescued the deficiencies in KO NKL cells. Using this in vitro model, we identified two epigenetic drugs, decitabine and panobinostat, by screening. Combination treatment using these two drugs significantly upregulated TUSC3 expression and rescued the immune and liver abnormalities.Epigenetic activation of TUSC3 expression constitutes an effective therapeutic strategy for XMEN disease.Copyright © 2023. Published by Elsevier Inc.