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.
摘要:
“X连锁免疫缺陷与镁缺陷,EB病毒(EBV)感染,和瘤形成(XMEN)疾病是由镁转运蛋白1(MAGT1)基因功能突变的丧失引起的糖基化和免疫的先天性错误。它是一种多系统疾病,强烈影响某些免疫细胞。MAGT1现在被确认为寡糖转移酶复合物的非催化亚基,并促进特定底物的天冬酰胺(N)连接的糖基化,使XMEN成为先天性糖基化障碍,表现为联合免疫缺陷。临床疾病具有可变的表达能力,除了Mg2+异常外,关键MAGT1依赖性糖蛋白的糖基化受损也可以解释一些免疫表现。NKG2D,对EBV的细胞毒性功能至关重要的激活受体,糖基化较差,并且在XMEN患者的CD8T细胞和自然杀伤(NK)细胞上总是减少。它是该疾病的最佳生物标志物。EBV初治XMEN患者的特征已经阐明了先前归因于EBV感染的遗传疾病的特征。额外的免疫表现,包括肝脏和神经系统异常,最近有报道。EBV相关淋巴瘤仍然是严重发病的主要原因。不幸的是,解决疾病潜在机制的治疗选择仍然有限,补充Mg2+尚未被证明是成功的。这里,我们回顾了扩大的临床表型和最近的糖生物学进展,这些进展增加了我们对XMEN疾病的认识。根据这些新发现,我们还建议将XMEN更新为“X连锁MAGT1缺乏症,对EBV感染和N连锁糖基化缺陷的易感性增加”。