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Duncan, Christopher J. A.; Thompson, Benjamin J.; Chen, Rui; Rice, Gillian; Gothe, Florian; Young, Dan F.; Lovell, Simon C.; Shuttleworth, Victoria G.; Brocklebank, Vicky; Corner, Bronte; Skelton, Andrew J.; Bondet, Vincent; Coxhead, Jonathan; Duffy, Darragh; Fourrage, Cecile; Livingston, John H.; Pavaine, Julija; Cheesman, Edmund; Bitetti, Stephania; Grainger, Angela; Acres, Meghan; Innes, Barbara A.; Mikulasova, Aneta; Sun, Ruyue; Hussain, Rafiqul; Wright, Ronnie; Wynn, Robert; Zarhrate, Mohammed; Zeef, Leo A. H.; Wood, Katrina; Hughes, Stephen M.; Harris, Claire L.; Engelhardt, Karin R.; Crow, Yanick J.; Randall, Richard E.; Kavanagh, David; Hambleton, Sophie and Briggs, Tracy A. (2019): Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2. In: Science Immunology, Vol. 4, No. 42, eaav7501

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Excessive type I interferon (IFN alpha/beta) activity is implicated in a spectrum of human disease, yet its direct role remains to be conclusively proven. We investigated two siblings with severe early-onset autoinflammatory disease and an elevated IFN signature. Whole-exome sequencing revealed a shared homozygous missense Arg148Trp variant in STAT2, a transcription factor that functions exclusively downstream of innate IFNs. Cells bearing STAT2(R148W) in homozygosity (but not heterozygosity) were hypersensitive to IFN alpha/beta, which manifest as prolonged Janus kinase-signal transducers and activators of transcription (STAT) signaling and transcriptional activation. We show that this gain of IFN activity results from the failure of mutant STAT2(R148W) to interact with ubiquitin-specific protease 18, a key STAT2-dependent negative regulator of IFN alpha/beta signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFN alpha/beta signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFN alpha/beta activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.

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