Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2
Christopher Duncan
(1)
,
Benjamin Thompson
(1)
,
Rui Chen
(1)
,
Gillian Rice
(2)
,
Florian Gothe
(1, 3)
,
Dan Young
(4)
,
Simon Lovell
(2)
,
Victoria Shuttleworth
(1)
,
Vicky Brocklebank
(1)
,
Bronte Corner
(1)
,
Andrew Skelton
(1)
,
Vincent Bondet
(5)
,
Jonathan Coxhead
(1)
,
Darragh Duffy
(5)
,
Cécile Fourrage
(6)
,
John Livingston
(7)
,
Julija Pavaine
(8, 2)
,
Edmund Cheesman
(8)
,
Stephania Bitetti
(8)
,
Angela Grainger
(1)
,
Meghan Acres
(1)
,
Barbara Innes
(1)
,
Aneta Mikulasova
(1)
,
Ruyue Sun
(1)
,
Rafiqul Hussain
(5)
,
Ronnie Wright
(2, 8)
,
Robert Wynn
(9)
,
Mohammed Zarhrate
(10)
,
Leo Zeef
(2)
,
Katrina Wood
(11)
,
Stephen Hughes
(9, 8)
,
Claire Harris
(1)
,
Karin Engelhardt
(1)
,
Yanick Crow
(10, 12, 13)
,
Richard Randall
(4)
,
David Kavanagh
(1, 11)
,
Sophie Hambleton
(1, 11)
,
Tracy Briggs
(2, 8)
1
Newcastle University [Newcastle]
2 University of Manchester [Manchester]
3 LMU - Ludwig Maximilian University [Munich] = Ludwig Maximilians Universität München
4 University of St Andrews [Scotland]
5 Immunobiologie des Cellules dendritiques
6 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
7 University of Leeds
8 Central Manchester University Hospitals NHS Foundation Trust
9 Royal Manchester Children's Hospital
10 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
11 Newcastle Upon Tyne Hospitals NHS Foundation Trust
12 UPD5 - Université Paris Descartes - Paris 5
13 University of Edinburgh
2 University of Manchester [Manchester]
3 LMU - Ludwig Maximilian University [Munich] = Ludwig Maximilians Universität München
4 University of St Andrews [Scotland]
5 Immunobiologie des Cellules dendritiques
6 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
7 University of Leeds
8 Central Manchester University Hospitals NHS Foundation Trust
9 Royal Manchester Children's Hospital
10 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
11 Newcastle Upon Tyne Hospitals NHS Foundation Trust
12 UPD5 - Université Paris Descartes - Paris 5
13 University of Edinburgh
Christopher Duncan
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- PersonId : 1062330
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Vincent Bondet
- Function : Author
- PersonId : 746608
- IdHAL : vincent-bondet
- ORCID : 0000-0002-6534-0984
Darragh Duffy
- Function : Author
- PersonId : 746816
- IdHAL : darragh-duffy
- ORCID : 0000-0002-8875-2308
- IdRef : 201316919
Yanick Crow
- Function : Author
- PersonId : 11918
- IdHAL : yanick-crow
- ORCID : 0000-0001-7211-7564
- IdRef : 227205359
Sophie Hambleton
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- Function : Correspondent author
- PersonId : 1062331
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Tracy Briggs
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- Function : Correspondent author
- PersonId : 1062332
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Abstract
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.