Ontology highlight
ABSTRACT: Background
Impaired signaling in the IFN-?/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-?/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-?-induced gene expression, but we found impaired responses to IFN-? restimulation.Conclusion
Gain-of-function mutations in STAT1 predispose to invasive, severe, disseminated dimorphic yeast infections, likely through aberrant regulation of IFN-?-mediated inflammation.
SUBMITTER: Sampaio EP
PROVIDER: S-EPMC3746066 | biostudies-literature | 2013 Jun
REPOSITORIES: biostudies-literature
The Journal of allergy and clinical immunology 20130328 6
<h4>Background</h4>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.<h4>Objective</h4>We sought to identify the molecular defect in patients with disseminated dimorphic yeast infections.<h4>Methods</h4>PBMCs, EBV-transformed B cells, and transfected ...[more]