Journal Article

Progressive Multifocal Leukoencephalopathy in Primary Immune Deficiencies: Stat1 Gain of Function and Review of the Literature

Hanks, Mary E., Zerbe, Christa S., Quezado, Martha M., Freeman, Alexandra F., Katial, Rohit K., Frein, Cathleen, Uzel, Gulbu, Holland, Steven M., Barnhart, Lisa A., Anderson, Victoria L., Adamo, Nick, Darnell, Dirk N., Lisco, Andrea, Santos, Carah B., Nath, Avindra, Major, Eugene O., Hsu, Amy P., Marciano, Beatriz E., Sampaio, Elizabeth P.

2016

Overview

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.

• Publisher: Oxford University Press
• Subject: Adult / and Commentaries / ARTICLES AND COMMENTARIES / Brain / Brain - diagnostic imaging / Cell Line, Tumor / Central nervous system / Female / Gene Expression Regulation / Humans / Immunologic Deficiency Syndromes - complications / Immunologic Deficiency Syndromes - diagnostic imaging / Immunologic Deficiency Syndromes - genetics / Interferon-gamma - pharmacology / JC virus / JC Virus - growth & development / Leukoencephalopathy, Progressive Multifocal - complications / Leukoencephalopathy, Progressive Multifocal - diagnostic imaging / Leukoencephalopathy, Progressive Multifocal - genetics / Leukoencephalopathy, Progressive Multifocal - immunology / Male / Medical diagnosis / Middle Aged / Mutation / Phosphorylation / Polyomaviridae / Polyomavirus / Sequence Analysis, DNA / Signal transduction / STAT1 Transcription Factor - genetics / STAT1 Transcription Factor - physiology / Transcriptional Activation / Viral infections / Viral Load / Young Adult