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

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 mycobacteria2,3,4,5. 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.

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Figure 1: Kindred, phenotype and genotype information.
Figure 2: Impaired expression of STAT1 and IFN-inducible genes.
Figure 3: Impaired activation of GAFs by IFN-γ and IFN-α.
Figure 4: Impaired activation of ISGF3 by IFN-α.
Figure 5: Molecular complementation of STAT1 deficiency.
Figure 6: Absence of antiviral effects of IFN-α/β.

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Acknowledgements

We thank L. Abel, C. Dargemont, C. Picard and C. Soudais for discussions and critical reading; S. Pellegrini, P. Lebon and E. Meurs for providing viruses; and J. Feinberg and M.T. Bandu for technical assistance. This work was supported by grants from Banque Nationale de Paris-Paribas, Fondation Schlumberger and Sequella Foundation.

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Correspondence to Jean-Laurent Casanova.

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Dupuis, S., Jouanguy, E., Al-Hajjar, S. et al. Impaired response to interferon-α/β and lethal viral disease in human STAT1 deficiency. Nat Genet 33, 388–391 (2003). https://doi.org/10.1038/ng1097

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