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.
Original language | English (US) |
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Pages (from-to) | 986-994 |
Number of pages | 9 |
Journal | Clinical Infectious Diseases |
Volume | 62 |
Issue number | 8 |
DOIs | |
State | Published - Apr 15 2016 |
Keywords
- PID
- PML
- STAT1 gain of function
- primary immunodeficiency
- progressive multifocal leukoencephalopathy
ASJC Scopus subject areas
- Microbiology (medical)
- Infectious Diseases