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

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