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Abstract：
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.
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.
摘要：
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。
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。
