Impaired response to interferon-α/β and lethal viral disease in human STAT1 deficiency

Stéphanie Dupuis, Emmanuelle Jouanguy, Sami Al-Hajjar, Claire Fieschi, Ibrahim Zaid Al-Mohsen, Suliman Al-Jumaah, Kun Yang, Ariane Chapgier, Céline Eidenschenk, Pierre Eid, Abdulaziz Al Ghonaium, Haysam Tufenkeji, Husn Frayha, Suleiman Al-Gazlan, Hassan Al-Rayes, Robert D. Schreiber, Ion Gresser, Jean Laurent Casanova

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531 Scopus citations

Abstract

The receptors for interferon-α/β (IFN-α/β) and IFN-γ activate components of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, leading to the formation of at least two transcription factor complexes1. STAT1 interacts with STAT2 and p48/IRF-9 to form the transcription factor IFN-stimulated gene factor 3 (ISGF3). STAT1 dimers form γ-activated factor (GAF). ISGF3 is induced mainly by IFN-α/β, and GAF by IFN-γ, although both factors can be activated by both types of IFN. Individuals with mutations in either chain of the IFN-γ receptor (IFN-γR) are susceptible to infection with mycobacteria2-5. A heterozygous STAT1 mutation that impairs GAF but not ISGF3 activation has been found in other individuals with mycobacterial disease6. No individuals with deleterious mutations in the IFN-α/β signaling pathway have been described. We report here two unrelated infants homozygous with respect to mutated STAT1 alleles. Neither IFN-α/β nor IFN-γ activated STAT1-containing transcription factors. Like individuals with IFN-γR deficiency, both infants suffered from mycobacterial disease, but unlike individuals with IFN-γR deficiency, both died of viral disease. Viral multiplication was not inhibited by recombinant IFN-α/β in cell lines from the two individuals. Inherited impairment of the STAT1-dependent response to human IFN-α/β thus results in susceptibility to viral disease.

Original languageEnglish
Pages (from-to)388-391
Number of pages4
JournalNature Genetics
Volume33
Issue number3
DOIs
StatePublished - Mar 1 2003

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    Dupuis, S., Jouanguy, E., Al-Hajjar, S., Fieschi, C., Zaid Al-Mohsen, I., Al-Jumaah, S., Yang, K., Chapgier, A., Eidenschenk, C., Eid, P., Al Ghonaium, A., Tufenkeji, H., Frayha, H., Al-Gazlan, S., Al-Rayes, H., Schreiber, R. D., Gresser, I., & Casanova, J. L. (2003). Impaired response to interferon-α/β and lethal viral disease in human STAT1 deficiency. Nature Genetics, 33(3), 388-391. https://doi.org/10.1038/ng1097