2. Academic Validation
  3. Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2

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

  • Sci Immunol. 2019 Dec 13;4(42):eaav7501. doi: 10.1126/sciimmunol.aav7501.
Christopher J A Duncan 1 2,  Benjamin J Thompson 3,  Rui Chen 3,  Gillian I Rice 4,  Florian Gothe 3 5,  Dan F Young 6,  Simon C Lovell 4,  Victoria G Shuttleworth 7,  Vicky Brocklebank 7,  Bronte Corner 7,  Andrew J Skelton 3,  Vincent Bondet 8,  Jonathan Coxhead 9,  Darragh Duffy 8,  Cecile Fourrage 10,  John H Livingston 11,  Julija Pavaine 12 13,  Edmund Cheesman 14,  Stephania Bitetti 14,  Angela Grainger 3,  Meghan Acres 3,  Barbara A Innes 3,  Aneta Mikulasova 3,  Ruyue Sun 7,  Rafiqul Hussain 8,  Ronnie Wright 4 15,  Robert Wynn 16,  Mohammed Zarhrate 17,  Leo A H Zeef 18,  Katrina Wood 19,  Stephen M Hughes 20,  Claire L Harris 7,  Karin R Engelhardt 3,  Yanick J Crow 21 22 23,  Richard E Randall 6,  David Kavanagh 7 24,  Sophie Hambleton 1 25,  Tracy A Briggs 26 15
Affiliations

Affiliations

  • 1 Primary Immunodeficiency Group, Immunity and Inflammation Theme, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK. christopher.duncan@ncl.ac.uk tracy.briggs@manchester.ac.uk sophie.hambleton@ncl.ac.uk.
  • 2 Department of Infection and Tropical Medicine, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
  • 3 Primary Immunodeficiency Group, Immunity and Inflammation Theme, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
  • 4 Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, UK.
  • 5 Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität Munich, Munich, Germany.
  • 6 School of Biology, University of St. Andrews, St. Andrews, UK.
  • 7 Complement Therapeutics Research Group, Immunity and Inflammation Theme, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
  • 8 Immunobiology of Dendritic Cells, Institut Pasteur, Paris, France.
  • 9 Genomics Core Facility, Biosciences Institute, Newcastle University, UK.
  • 10 Plateforme Bioinformatique, Institut Imagine, Paris, France.
  • 11 Department of Paediatric Neurology, Leeds General Infirmary, Leeds, UK.
  • 12 Academic Unit of Paediatric Radiology, Royal Manchester Children's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
  • 13 Division of Informatics, Imaging and Data Sciences, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
  • 14 Department of Paediatric Histopathology, Central Manchester University Foundation NHS Trust, Manchester, UK.
  • 15 Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
  • 16 Department of Paediatric Blood and Marrow Transplant, Royal Manchester Children's Hospital, Oxford Rd., Manchester, UK.
  • 17 Genomics Core Facility, Institut Imagine, Paris, France.
  • 18 Bioinformatics Core Facility, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
  • 19 Department of Pathology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
  • 20 Immunology Department, Royal Manchester Children's Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
  • 21 MRC Institute of Genetics and Molecular Medicine, Centre for Genomic and Experimental Medicine, The University of Edinburgh, Edinburgh, UK.
  • 22 Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, Paris, France.
  • 23 Paris Descartes University, Sorbonne-Paris-Cité, Paris, France.
  • 24 National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne Hosptials NHS Foundation Trust, Newcastle upon Tyne, UK.
  • 25 Children's Immunology Service, Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
  • 26 Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, UK. christopher.duncan@ncl.ac.uk tracy.briggs@manchester.ac.uk sophie.hambleton@ncl.ac.uk.
PMID: 31836668 DOI: 10.1126/sciimmunol.aav7501
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.

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