Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis

Elizabeth P. Sampaio, Amy P. Hsu, Joseph Pechacek, Hannelore I. Bax, Dalton L. Dias, Michelle L. Paulson, Prabha Chandrasekaran, Lindsey B. Rosen, Daniel S. Carvalho, Li Ding, Donald C. Vinh, Sarah K. Browne, Shrimati Datta, Joshua D. Milner, Douglas B. Kuhns, Debra A. Long Priel, Mohammed A. Sadat, Michael Shiloh, Brendan De Marco, Michael Alvares & 15 others Jason W. Gillman, Vivek Ramarathnam, Maite De La Morena, Liliana Bezrodnik, Ileana Moreira, Gulbu Uzel, Daniel Johnson, Christine Spalding, Christa S. Zerbe, Henry Wiley, David E. Greenberg, Susan E. Hoover, Sergio D. Rosenzweig, John N. Galgiani, Steven M. Holland

Research output: Contribution to journalArticle

109 Citations (Scopus)

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.

Original languageEnglish (US)
JournalJournal of Allergy and Clinical Immunology
Volume131
Issue number6
DOIs
StatePublished - Jun 2013

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STAT1 Transcription Factor
Coccidioidomycosis
Histoplasmosis
Mutation
Yeasts
Interleukin-12
Transcriptional Activation
Chronic Mucocutaneous Candidiasis
Phosphorylation
Coccidioides
Histoplasma
Mycobacterium Infections
Proteins
DNA
Missense Mutation
Infection
Human Herpesvirus 4
Interferons
B-Lymphocytes
Inflammation

Keywords

  • Coccidioides immitis
  • Histoplasma capsulatum
  • IFN-γ
  • progressive multifocal leukoencephalopathy
  • Signal transducer and activator of transcription 1
  • thrush

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis. / Sampaio, Elizabeth P.; Hsu, Amy P.; Pechacek, Joseph; Bax, Hannelore I.; Dias, Dalton L.; Paulson, Michelle L.; Chandrasekaran, Prabha; Rosen, Lindsey B.; Carvalho, Daniel S.; Ding, Li; Vinh, Donald C.; Browne, Sarah K.; Datta, Shrimati; Milner, Joshua D.; Kuhns, Douglas B.; Long Priel, Debra A.; Sadat, Mohammed A.; Shiloh, Michael; De Marco, Brendan; Alvares, Michael; Gillman, Jason W.; Ramarathnam, Vivek; De La Morena, Maite; Bezrodnik, Liliana; Moreira, Ileana; Uzel, Gulbu; Johnson, Daniel; Spalding, Christine; Zerbe, Christa S.; Wiley, Henry; Greenberg, David E.; Hoover, Susan E.; Rosenzweig, Sergio D.; Galgiani, John N.; Holland, Steven M.

In: Journal of Allergy and Clinical Immunology, Vol. 131, No. 6, 06.2013.

Research output: Contribution to journalArticle

Sampaio, EP, Hsu, AP, Pechacek, J, Bax, HI, Dias, DL, Paulson, ML, Chandrasekaran, P, Rosen, LB, Carvalho, DS, Ding, L, Vinh, DC, Browne, SK, Datta, S, Milner, JD, Kuhns, DB, Long Priel, DA, Sadat, MA, Shiloh, M, De Marco, B, Alvares, M, Gillman, JW, Ramarathnam, V, De La Morena, M, Bezrodnik, L, Moreira, I, Uzel, G, Johnson, D, Spalding, C, Zerbe, CS, Wiley, H, Greenberg, DE, Hoover, SE, Rosenzweig, SD, Galgiani, JN & Holland, SM 2013, 'Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis', Journal of Allergy and Clinical Immunology, vol. 131, no. 6. https://doi.org/10.1016/j.jaci.2013.01.052
Sampaio, Elizabeth P. ; Hsu, Amy P. ; Pechacek, Joseph ; Bax, Hannelore I. ; Dias, Dalton L. ; Paulson, Michelle L. ; Chandrasekaran, Prabha ; Rosen, Lindsey B. ; Carvalho, Daniel S. ; Ding, Li ; Vinh, Donald C. ; Browne, Sarah K. ; Datta, Shrimati ; Milner, Joshua D. ; Kuhns, Douglas B. ; Long Priel, Debra A. ; Sadat, Mohammed A. ; Shiloh, Michael ; De Marco, Brendan ; Alvares, Michael ; Gillman, Jason W. ; Ramarathnam, Vivek ; De La Morena, Maite ; Bezrodnik, Liliana ; Moreira, Ileana ; Uzel, Gulbu ; Johnson, Daniel ; Spalding, Christine ; Zerbe, Christa S. ; Wiley, Henry ; Greenberg, David E. ; Hoover, Susan E. ; Rosenzweig, Sergio D. ; Galgiani, John N. ; Holland, Steven M. / Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis. In: Journal of Allergy and Clinical Immunology. 2013 ; Vol. 131, No. 6.
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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.",
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T1 - Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis

AU - Sampaio, Elizabeth P.

AU - Hsu, Amy P.

AU - Pechacek, Joseph

AU - Bax, Hannelore I.

AU - Dias, Dalton L.

AU - Paulson, Michelle L.

AU - Chandrasekaran, Prabha

AU - Rosen, Lindsey B.

AU - Carvalho, Daniel S.

AU - Ding, Li

AU - Vinh, Donald C.

AU - Browne, Sarah K.

AU - Datta, Shrimati

AU - Milner, Joshua D.

AU - Kuhns, Douglas B.

AU - Long Priel, Debra A.

AU - Sadat, Mohammed A.

AU - Shiloh, Michael

AU - De Marco, Brendan

AU - Alvares, Michael

AU - Gillman, Jason W.

AU - Ramarathnam, Vivek

AU - De La Morena, Maite

AU - Bezrodnik, Liliana

AU - Moreira, Ileana

AU - Uzel, Gulbu

AU - Johnson, Daniel

AU - Spalding, Christine

AU - Zerbe, Christa S.

AU - Wiley, Henry

AU - Greenberg, David E.

AU - Hoover, Susan E.

AU - Rosenzweig, Sergio D.

AU - Galgiani, John N.

AU - Holland, Steven M.

PY - 2013/6

Y1 - 2013/6

N2 - 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.

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KW - Coccidioides immitis

KW - Histoplasma capsulatum

KW - IFN-γ

KW - progressive multifocal leukoencephalopathy

KW - Signal transducer and activator of transcription 1

KW - thrush

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