背景:进行性多灶性白质脑病(PML)是一种罕见的,严重,否则,由多瘤病毒JC病毒引起的脑白质的致命病毒感染,这通常只发生在免疫受损的患者。先前报道了一名患有信号转导和转录激活因子1(STAT1)的显性功能获得(GOF)突变并伴有慢性粘膜皮肤念珠菌病和PML的患者。我们旨在确定3例PML患者的分子缺陷,并回顾有关原发性免疫缺陷(PID)中PML的文献。
方法:对3例PML患者进行STAT1测序。用STAT1转染U3C细胞系,并测定寻找STAT1磷酸化,转录反应,并进行靶基因表达。
结果:我们在GOFSTAT1突变患者中发现了3例新的无关PML病例,包括新的STAT1突变,L400Q.这些STAT1突变导致延迟的STAT1去磷酸化和增强的干扰素-γ驱动的反应。在我们对原发性免疫缺陷PML的文献回顾中,我们发现26例,其中只有54%被分子表征,其余的仅被诊断为综合征。
结论:4例STAT1GOF中PML的发生表明STAT1在中枢神经系统JC病毒的控制中起关键作用。
BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a rare, severe, otherwise fatal viral infection of the white matter of the brain caused by the polyomavirus JC virus, which typically occurs only in immunocompromised patients. One patient with dominant gain-of-function (GOF) mutation in signal transducer and activator of transcription 1 (STAT1) with chronic mucocutaneous candidiasis and PML was reported previously. We aim to identify the molecular defect in 3 patients with PML and to review the literature on PML in primary immune defects (PIDs).
METHODS: STAT1 was sequenced in 3 patients with PML. U3C cell lines were transfected with STAT1 and assays to search for STAT1 phosphorylation, transcriptional response, and target gene expression were performed.
RESULTS: We identified 3 new unrelated cases of PML in patients with GOF STAT1 mutations, including the novel STAT1 mutation, L400Q. These STAT1 mutations caused delayed STAT1 dephosphorylation and enhanced interferon-gamma-driven responses. In our review of the literature regarding PML in primary immune deficiencies we found 26 cases, only 54% of which were molecularly characterized, the remainder being syndromically diagnosed only.
CONCLUSIONS: The occurrence of PML in 4 cases of STAT1 GOF suggests that STAT1 plays a critical role in the control of JC virus in the central nervous system.