title: Familial chilblain lupus due to a gain-of-function mutation in STING.
abstract: OBJECTIVE
  Familial chilblain lupus is a monogenic form of cutaneous lupus erythematosus caused by loss-of-function mutations in the nucleases TREX1 or SAMHD1. In a family without TREX1 or SAMHD1 mutation, we sought to determine the causative gene and the underlying disease pathology.
  
  
  METHODS
  Exome sequencing was used for disease gene identification. Structural analysis was performed by homology modelling and docking simulations. Type I interferon (IFN) activation was assessed in cells transfected with STING cDNA using an IFN-β reporter and Western blotting. IFN signatures in patient blood in response to tofacitinib treatment were measured by RT-PCR of IFN-stimulated genes.
  
  
  RESULTS
  In a multigenerational family with five members affected with chilblain lupus, we identified a heterozygous mutation of STING, a signalling molecule in the cytosolic DNA sensing pathway. Structural and functional analyses indicate that mutant STING enhances homodimerisation in the absence of its ligand cGAMP resulting in constitutive type I IFN activation. Treatment of two affected family members with the Janus kinase (JAK) inhibitor tofacitinib led to a marked suppression of the IFN signature.
  
  
  CONCLUSIONS
  A heterozygous gain-of-function mutation in STING can cause familial chilblain lupus. These findings expand the genetic spectrum of type I IFN-dependent disorders and suggest that JAK inhibition may be of therapeutic value.
authors: Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors: Nadja
authors: N
authors: König
authors: ACURA Akutklinik für Rheumatologie Baden-Baden, Baden-Baden, Germany.
authors: Christoph
authors: C
authors: Fiehn
authors: Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors: Christine
authors: C
authors: Wolf
authors: Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors: Max
authors: M
authors: Schuster
authors: System Biology Group (SysBio), Institute of Physics of Liquids and Biological Systems (IFLYSIB) CONICET, University of La Plata, La Plata, Argentina.
authors: Emanuel
authors: E
authors: Cura Costa
authors: Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors: Victoria
authors: V
authors: Tüngler
authors: System Biology Group (SysBio), Institute of Physics of Liquids and Biological Systems (IFLYSIB) CONICET, University of La Plata, La Plata, Argentina.
authors: Hugo Ariel
authors: HA
authors: Alvarez
authors: System Biology Group (SysBio), Institute of Physics of Liquids and Biological Systems (IFLYSIB) CONICET, University of La Plata, La Plata, Argentina.|Center for Information Services and High Performance Computing, Technische Universität Dresden, Dresden, Germany.
authors: Osvaldo
authors: O
authors: Chara
authors: Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors: Kerstin
authors: K
authors: Engel
authors: Translational Autoinflammatory Disease Section, NIAMS, NIH, Bethesda, Maryland, USA.
authors: Raphaela
authors: R
authors: Goldbach-Mansky
authors: Department of Dermatology, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors: Claudia
authors: C
authors: Günther
authors: Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors: Min Ae
authors: MA
authors: Lee-Kirsch
mesh_terms: D000328:Adult; D015153:Blotting, Western; D002647:Chilblains / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D005190:Family; D005260:Female; D006115:Greece; D006801:Humans; D007370:Interferon Type I / Q000276:immunology; D016899:Interferon-beta / Q000276:immunology; D008178:Lupus Erythematosus, Cutaneous / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D020678:Microscopic Angioscopy; D062105:Molecular Docking Simulation; D009154:Mutation; D010375:Pedigree; D010880:Piperidines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000473:pathology; D000099197:STING Protein
chemical_list: D007370:Interferon Type I; D016899:Interferon-beta; D008565:Membrane Proteins; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C532857:STING1 protein, human; D000099197:STING Protein; C479163:tofacitinib
keywords: Autoimmunity; Cytokines; Inflammation; Systemic Lupus Erythematosus