Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2

Christopher J.A. Duncan*, Benjamin J. Thompson, Rui Chen, Gillian I. Rice, Florian Gothe, Dan F. Young, Simon C. Lovell, Victoria G. Shuttleworth, Vicky Brocklebank, Bronte Corner, Andrew J. Skelton, Vincent Bondet, Jonathan Coxhead, Darragh Duffy, Cecile Fourrage, John H. Livingston, Julija Pavaine, Edmund Cheesman, Stephania Bitetti, Angela GraingerMeghan Acres, Barbara A. Innes, Aneta Mikulasova, Ruyue Sun, Rafiqul Hussain, Ronnie Wright, Robert Wynn, Mohammed Zarhrate, Leo A.H. Zeef, Katrina Wood, Stephen M. Hughes, Claire L. Harris, Karin R. Engelhardt, Yanick J. Crow, Richard E. Randall, David Kavanagh, Sophie Hambleton*, Tracy A. Briggs*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)


Excessive type I interferon (IFNα/β) 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 STAT2R148W in homozygosity (but not heterozygosity) were hypersensitive to IFNα/β, 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 STAT2R148W to interact with ubiquitin-specific protease 18, a key STAT2-dependent negative regulator of IFNα/β signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFNα/β signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFNα/β activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.
Original languageEnglish
Article numbereaav7501
JournalScience Immunology
Issue number42
Publication statusPublished - 13 Dec 2019


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