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

Lookup NU author(s): Dr Christopher DuncanORCiD, Dr Benjamin Thompson, Dr Rui ChenORCiD, Dr Florian Gothe, Victoria Shuttleworth, Dr Vicky Brocklebank, Dr Meghan Acres, Barbara Innes, Dr Aneta Mikulasova, Dr Ruyue Sun, Professor Claire Harris, Dr Karin Engelhardt, Professor David KavanaghORCiD, Professor Sophie HambletonORCiD



This is the authors' accepted manuscript of an article that has been published in its final definitive form by American Association for the Advancement of Science, 2019.

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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 STAT2R148Win homozygosity (but not heterozygosity) were hypersensitive to IFNα/β, manifest as prolonged JAK-STAT signaling and transcriptional activation. We show that this gain of IFN activity results from the failure of mutant STAT2R148Wto interact with ubiquitin specific protease 18 (USP18), a key STAT2-dependent negative regulator of IFNα/β signaling. These observations reveal an essential in vivofunction 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.

Publication metadata

Author(s): Duncan CJA, Thompson BJ, Chen R, Rice GI, Gothe F, Young DF, Lovell SC, Shuttleworth VG, Brocklebank V, Corner B, Skelton AJ, Bondet V, Coxhead J, Duffy D, Fourrage C, Livingston JH, Pavaine J, Cheesman E, Bitetti S, Grainger A, Acres M, Innes BA, Mikulasova A, Sun R, Hussain H, Wright R, Wynn R, Zarhrate M, Zeef LAH, Wood K, Hughes SM, Harris CL, Engelhardt KE, Crow YJ, Randall RE, Kavanagh D, Hambleton S, Briggs TA

Publication type: Article

Publication status: Published

Journal: Science Immunology

Year: 2019

Volume: 4

Issue: 42

Online publication date: 13/12/2019

Acceptance date: 14/11/2019

Date deposited: 27/11/2019

ISSN (electronic): 2470-9468

Publisher: American Association for the Advancement of Science


DOI: 10.1126/sciimmunol.aav7501


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