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Dupuis, S. et al.

Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency.

The receptors for interferon-alpha/beta (IFN-alpha/beta) and IFN-gamma 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 complexes. STAT1 interacts with STAT2 and p48/IRF-9 to form the transcription factor IFN-stimulated gene factor 3 ( ISGF3). STAT1 dimers form gamma-activated factor (GAF). ISGF3 is induced mainly by IFN-alpha/beta, and GAF by IFN-gamma, although both factors can be activated by both types of IFN. Individuals with mutations in either chain of the IFN-gamma receptor (IFN-gammaR) are susceptible to infection with mycobacteria. A heterozygous STAT1 mutation that impairs GAF but not ISGF3 activation has been found in other individuals with mycobacterial disease. No individuals with deleterious mutations in the IFN-alpha/beta signaling pathway have been described. We report here two unrelated infants homozygous with respect to mutated STAT1 alleles. Neither IFN-alpha/beta nor IFN-gamma activated STAT1-containing transcription factors. Like individuals with IFN-gammaR deficiency, both infants suffered from mycobacterial disease, but unlike individuals with IFN-gammaR deficiency, both died of viral disease. Viral multiplication was not inhibited by recombinant IFN-alpha/beta in cell lines from the two individuals. Inherited impairment of the STAT1-dependent response to human IFN-alpha/beta thus results in susceptibility to viral disease.[1]

References

Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency. Dupuis, S., Jouanguy, E., Al-Hajjar, S., Fieschi, C., Al-Mohsen, I.Z., 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. Nat. Genet. (2003) [Pubmed]

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