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.

Coccidioides immitis, Histoplasma capsulatum, IFN-γ, progressive multifocal leukoencephalopathy, Signal transducer and activator of transcription 1, thrush,
Journal of Allergy and Clinical Immunology
Department of Internal Medicine

Sampaio, E.P, Hsu, A.P, Pechacek, J, Bax, H.I, Dias, D.L, Paulson, M.L, … Holland, S.M. (2013). Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis. Journal of Allergy and Clinical Immunology, 131(6). doi:10.1016/j.jaci.2013.01.052