title: Disease-associated mutations identify a novel region in human STING necessary for the control of type I interferon signaling.
abstract: Gain-of-function mutations in transmembrane protein 173 (TMEM173) encoding stimulator of interferon genes (STING) underlie a recently described type I interferonopathy called STING-associated vasculopathy with onset in infancy (SAVI).
  
  
  
  We sought to define the molecular and cellular pathology relating to 3 individuals variably exhibiting the core features of the SAVI phenotype including systemic inflammation, destructive skin lesions, and interstitial lung disease.
  
  
  
  Genetic analysis, conformational studies, in vitro assays and ex vivo flow-cytometry were performed.
  
  
  
  Molecular and in vitro data demonstrate that the pathology in these patients is due to amino acid substitutions at positions 206, 281, and 284 of the human STING protein. These mutations confer cGAMP-independent constitutive activation of type I interferon signaling through TBK1 (TANK-binding kinase), independent from the alternative STING pathway triggered by membrane fusion of enveloped RNA viruses. This constitutive activation was abrogated by ex vivo treatment with the janus kinase 1/2 inhibitor ruxolitinib.
  
  
  
  Structural analysis indicates that the 3 disease-associated mutations at positions 206, 281, and 284 of the STING protein define a novel cluster of amino acids with functional importance in the regulation of type I interferon signaling.
authors.affiliation: INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, France; Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France; General Pediatrics, Infectious Disease and Internal Medicine Department, Hôpital Robert Debré, AP-HP, Paris, France; Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Melki
authors.affiliation: INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, France; Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France.
authors.forename: Yoann
authors.initials: Y
authors.lastname: Rose
authors.affiliation: INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, France; Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France.
authors.forename: Carolina
authors.initials: C
authors.lastname: Uggenti
authors.affiliation: INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, France; Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France; Department of Immunology and Microbiology, Childhood Immunology, University of Leuven, Leuven, Belgium.
authors.forename: Lien
authors.initials: L
authors.lastname: Van Eyck
authors.affiliation: INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, France; Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France; Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Frémond
authors.affiliation: INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, France; Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kitabayashi
authors.affiliation: Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Evolution and Genomic Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Gillian I
authors.initials: GI
authors.lastname: Rice
authors.affiliation: Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Evolution and Genomic Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Emma M
authors.initials: EM
authors.lastname: Jenkinson
authors.affiliation: INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, France; Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France.
authors.forename: Anaïs
authors.initials: A
authors.lastname: Boulai
authors.affiliation: Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France; INSERM UMR 1163, Laboratory of Immunogenetics of Pediatric Autoimmunity, Paris, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Jeremiah
authors.affiliation: UO Pediatria 2 Reumatologia, G. Gaslini, Genova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gattorno
authors.affiliation: UO Pediatria 2 Reumatologia, G. Gaslini, Genova, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Volpi
authors.affiliation: UO Pneumologia, G. Gaslini, Genova, Italy.
authors.forename: Olivero
authors.initials: O
authors.lastname: Sacco
authors.affiliation: Department of Paediatric, Pulmonology Emma Children's Hospital AMC DD, Amsterdam, The Netherlands.
authors.forename: Suzanne W J
authors.initials: SWJ
authors.lastname: Terheggen-Lagro
authors.affiliation: Department of Radiology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Paediatrics, Respiratory Medicine and Allergology, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Harm A W M
authors.initials: HAWM
authors.lastname: Tiddens
authors.affiliation: Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium; Department of Immunology and Microbiology, Childhood Immunology, University of Leuven, Leuven, Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Meyts
authors.affiliation: Department of Dermatology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Morren
authors.affiliation: Department of Immunology and Microbiology, Childhood Immunology, University of Leuven, Leuven, Belgium; Department of Dermatology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Petra
authors.initials: P
authors.lastname: De Haes
authors.affiliation: Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, AP-HP, Paris, France; Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium; Department of Immunology and Microbiology, Childhood Immunology, University of Leuven, Leuven, Belgium.
authors.forename: Carine
authors.initials: C
authors.lastname: Wouters
authors.affiliation: Department of Human Genetics, KU Leuven, Leuven, Belgium; Clinical Department of Human Genetics, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Eric
authors.initials: E
authors.lastname: Legius
authors.affiliation: Clinical Department of Human Genetics, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Anniek
authors.initials: A
authors.lastname: Corveleyn
authors.affiliation: Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France; INSERM UMR 1163, Laboratory of Immunogenetics of Pediatric Autoimmunity, Paris, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Rieux-Laucat
authors.affiliation: Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France; Dermatology Department, National Reference Center for Rare Skin Diseases MAGEC, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Bodemer
authors.affiliation: CNRS UMR7590, Sorbonne Université, Université Pierre et Marie Curie-Paris6-MNHN-IRD-IUC, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Callebaut
authors.affiliation: INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, France; Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France.
authors.forename: Mathieu P
authors.initials: MP
authors.lastname: Rodero
authors.affiliation: INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, France; Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France; Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Evolution and Genomic Sciences, University of Manchester, Manchester, United Kingdom. Electronic address: yanickcrow@mac.com.
authors.forename: Yanick J
authors.initials: YJ
authors.lastname: Crow
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D002648:Child; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D007370:Interferon Type I / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D000099197:STING Protein
chemical_list: D007370:Interferon Type I; D008565:Membrane Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C532857:STING1 protein, human; D000099197:STING Protein
keywords: STING-associated vasculopathy with onset in infancy; Stimulator of interferon genes (STING); TMEM173; interferon; type I interferonopathy