Skip to content

Research at St Andrews

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

Research output: Contribution to journalArticle


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 Grainger & 18 more Meghan 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

School/Research organisations


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

Discover related content
Find related publications, people, projects and more using interactive charts.

View graph of relations

Related by author

  1. Innate intracellular antiviral responses restrict the amplification of defective virus genomes of parainfluenza virus type 5

    Wignall-Fleming, E. B., Vasou, A., Young, D., Short, J. A. L., Hughes, D. J., Goodbourn, S. & Randall, R. E., 16 Jun 2020, In : Journal of Virology. 94, 13, 15 p., 00246-20.

    Research output: Contribution to journalArticle

  2. Analysis of paramyxovirus transcription and replication by high-throughput sequencing

    Wignall-Fleming, E. B., Hughes, D. J., Vattipally, S., Modha, S., Goodbourn, S., Davison, A. J. & Randall, R. E., 13 Aug 2019, In : Journal of Virology. 93, 17, 17 p., e00571-19.

    Research output: Contribution to journalArticle

  3. Unusual, stable replicating viruses generated from mumps virus cDNA clones

    Bamford, C., Wignall-Fleming, E., Sreenu, V. B., Randall, R., Duprex, P. & Rima, B., 5 Jul 2019, In : PLoS ONE. 14, 7, 14 p., e0219168.

    Research output: Contribution to journalArticle

  4. The switch between acute and persistent paramyxovirus infection caused by single amino acid substitutions in the RNA polymerase P subunit

    Young, D. F., Wignall-Fleming, E. B., Busse, D. C., Pickin, M. J., Hankinson, J., Randall, E. M., Tavendale, A., Davison, A. J., Lamont, D., Tregoning, J. S., Goodbourn, S. & Randall, R. E., 11 Feb 2019, In : PLoS Pathogens. 15, 2, 24 p., e1007561.

    Research output: Contribution to journalArticle

ID: 265329294