title: Progressive Multifocal Leukoencephalopathy in Primary Immune Deficiencies: Stat1 Gain of Function and Review of the Literature.
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.
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Christa S
authors.initials: CS
authors.lastname: Zerbe
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Beatriz E
authors.initials: BE
authors.lastname: Marciano
authors.affiliation: National Jewish Health and University of Colorado, Health Sciences Center, Denver.
authors.forename: Rohit K
authors.initials: RK
authors.lastname: Katial
authors.affiliation: National Jewish Health and University of Colorado, Health Sciences Center, Denver.
authors.forename: Carah B
authors.initials: CB
authors.lastname: Santos
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Nick
authors.initials: N
authors.lastname: Adamo
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Amy P
authors.initials: AP
authors.lastname: Hsu
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Hanks
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Dirk N
authors.initials: DN
authors.lastname: Darnell
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda.
authors.forename: Martha M
authors.initials: MM
authors.lastname: Quezado
authors.affiliation: Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick.
authors.forename: Cathleen
authors.initials: C
authors.lastname: Frein
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Barnhart
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Anderson
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Gulbu
authors.initials: G
authors.lastname: Uzel
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Alexandra F
authors.initials: AF
authors.lastname: Freeman
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Lisco
authors.affiliation: Translational Neuroscience Center.
authors.forename: Avindra
authors.initials: A
authors.lastname: Nath
authors.affiliation: Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
authors.forename: Eugene O
authors.initials: EO
authors.lastname: Major
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Sampaio
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
mesh_terms: D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging; D045744:Cell Line, Tumor; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics*; D007371:Interferon-gamma / Q000494:pharmacology; D007577:JC Virus / Q000254:growth & development; D007968:Leukoencephalopathy, Progressive Multifocal / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000502:physiology*; D017422:Sequence Analysis, DNA; D015533:Transcriptional Activation; D019562:Viral Load; D055815:Young Adult
chemical_list: D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007371:Interferon-gamma
keywords: PID; PML; STAT1 gain of function; primary immunodeficiency; progressive multifocal leukoencephalopathy