@article{ad6c8f119c1c4386a82b8122179d5717,
title = "Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis",
abstract = "Background: Impaired signaling in the IFN-γ/IL-12 pathway causes susceptibility to severe disseminated infections with mycobacteria and dimorphic yeasts. Dominant gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1) have been associated with chronic mucocutaneous candidiasis. Objective: We sought to identify the molecular defect in patients with disseminated dimorphic yeast infections. Methods: PBMCs, EBV-transformed B cells, and transfected U3A cell lines were studied for IFN-γ/IL-12 pathway function. STAT1 was sequenced in probands and available relatives. Interferon-induced STAT1 phosphorylation, transcriptional responses, protein-protein interactions, target gene activation, and function were investigated. Results: We identified 5 patients with disseminated Coccidioides immitis or Histoplasma capsulatum with heterozygous missense mutations in the STAT1 coiled-coil or DNA-binding domains. These are dominant gain-of-function mutations causing enhanced STAT1 phosphorylation, delayed dephosphorylation, enhanced DNA binding and transactivation, and enhanced interaction with protein inhibitor of activated STAT1. The mutations caused enhanced IFN-γ-induced gene expression, but we found impaired responses to IFN-γ restimulation. Conclusion: Gain-of-function mutations in STAT1 predispose to invasive, severe, disseminated dimorphic yeast infections, likely through aberrant regulation of IFN-γ-mediated inflammation.",
keywords = "Coccidioides immitis, Histoplasma capsulatum, IFN-γ, Signal transducer and activator of transcription 1, progressive multifocal leukoencephalopathy, thrush",
author = "Sampaio, {Elizabeth P.} and Hsu, {Amy P.} and Joseph Pechacek and Bax, {Hannelore I.} and Dias, {Dalton L.} and Paulson, {Michelle L.} and Prabha Chandrasekaran and Rosen, {Lindsey B.} and Carvalho, {Daniel S.} and Li Ding and Vinh, {Donald C.} and Browne, {Sarah K.} and Shrimati Datta and Milner, {Joshua D.} and Kuhns, {Douglas B.} and {Long Priel}, {Debra A.} and Sadat, {Mohammed A.} and Michael Shiloh and {De Marco}, Brendan and Michael Alvares and Gillman, {Jason W.} and Vivek Ramarathnam and {De La Morena}, Maite and Liliana Bezrodnik and Ileana Moreira and Gulbu Uzel and Daniel Johnson and Christine Spalding and Zerbe, {Christa S.} and Henry Wiley and Greenberg, {David E.} and Hoover, {Susan E.} and Rosenzweig, {Sergio D.} and Galgiani, {John N.} and Holland, {Steven M.}",
note = "Funding Information: Disclosure of potential conflict of interest: D. C. Vinh has received research support from the Canadian Institutes of Health Research Post-doctoral Fellowship , CSL Behring Canada, and Astellas Canada ; has consultant arrangements with CSL Behring Canada and Pfizer Canada; and has received payment for lectures from CSL Behring Canada and Sunovion/Sepracor . D. B. Kuhns and D. A. Long Priel have received grants from the National Cancer Institute/National Institutes of Health . V. Ramarathnam is employed by Private Practice ID. S. D. Rosenzweig receives royalties from UpToDate . The rest of the authors declare that they have no relevant conflicts of interest. Funding Information: Supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health , and funded in part with federal funds from the National Cancer Institute, National Institutes of Health , under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. ",
year = "2013",
month = jun,
doi = "10.1016/j.jaci.2013.01.052",
language = "English (US)",
volume = "131",
pages = "1624--1634.e17",
journal = "Journal of Allergy and Clinical Immunology",
issn = "0091-6749",
publisher = "Mosby Inc.",
number = "6",
}