title: Mutations in CECR1 associated with a neutrophil signature in peripheral blood.
abstract: BACKGROUND
  A reduction of ADA2 activity due to autosomal recessive loss of function mutations in CECR1 results in a newly described vasculopathic phenotype reminiscent of polyarteritis nodosa, with manifestations ranging from fatal systemic vasculitis with multiple strokes in children to limited cutaneous disease in middle-aged individuals. Evidence indicates that ADA2 is essential for the endothelial integrity of small vessels. However, CECR1 is not expressed, nor is the ADA2 protein detectable, in cultured human endothelial cells, thus implicating additional cell types or circulating factors in disease pathogenesis.
  
  
  METHODS
  Considering the phenotypic overlap of ADA2 deficiency with the type I interferonopathy Aicardi-Goutières syndrome due to mutations in SAMHD1, we looked for the presence of an interferon signature in the peripheral blood of two newly ascertained ADA2-deficient patients.
  
  
  RESULTS
  We identified biallelic CECR1 mutations in two patients consistent with ADA2 deficiency. Both patients demonstrated an upregulation of interferon stimulated gene transcripts in peripheral blood. More strikingly however, genome-wide analysis revealed a marked overexpression of neutrophil-derived genes, suggesting that the vasculitis seen in ADA2 deficiency may be an indirect effect resulting from chronic and marked activity of neutrophils.
  
  
  CONCLUSIONS
  We hypothesise that ADA2 may act as a regulator of neutrophil activation, and that a reduction of ADA2 activity results in significant endothelial damage via a neutrophil-driven process.
authors.affiliation: Hospices Civils de Lyon, et Université de Lyon, Lyon, France ; CIRI, International Center for Infectiology Research, Inserm, U1111, Ecole Normale Supérieure de Lyon, Université Lyon 1, CNRS, UMR5308 Lyon, France ; Centre de Référence des maladies Rénales Rares, Service de Néphrologie, Rhumatologie & Dermatologie Pédiatriques, Lyon, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Belot
authors.affiliation: Department of Paediatric Neurology, Birmingham Children's Hospital, Birmingham, UK.
authors.forename: Evangeline
authors.initials: E
authors.lastname: Wassmer
authors.affiliation: Department of Adolescent and Pediatric Rheumatology, Birmingham Children's Hospital, Birmingham, UK ; Department of Pediatrics, Division of rheumatology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Marinka
authors.initials: M
authors.lastname: Twilt
authors.affiliation: Hospices Civils de Lyon, et Université de Lyon, Lyon, France ; Service de Médecine Interne et Vasculaire, Centre Hospitalier Lyon Sud, Lyon, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Lega
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: Leo Ah
authors.initials: LA
authors.lastname: Zeef
authors.affiliation: Manchester Centre for Genomic Médecine Interne et Vasculaire of Human Development Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Oojageer
authors.affiliation: Manchester Centre for Genomic Médecine Interne et Vasculaire of Human Development Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Kasher
authors.affiliation: CIRI, International Center for Infectiology Research, Inserm, U1111, Ecole Normale Supérieure de Lyon, Université Lyon 1, CNRS, UMR5308 Lyon, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Mathieu
authors.affiliation: Hospices Civils de Lyon, et Université de Lyon, Lyon, France ; Laboratoire d'Immunologie, Hôpital E. Herriot Lyon, Lyon, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Malcus
authors.affiliation: Hospices Civils de Lyon, et Université de Lyon, Lyon, France ; Laboratoire d'Immunologie, Hôpital E. Herriot Lyon, Lyon, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Demaret
authors.affiliation: Hospices Civils de Lyon, et Université de Lyon, Lyon, France ; Laboratoire d'Immunologie, Centre Hospitalier Lyon Sud, Lyon, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Fabien
authors.affiliation: Hospices Civils de Lyon, et Université de Lyon, Lyon, France ; Centre de Pathologie Est, Groupement Hospitalier EST, Lyon, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Collardeau-Frachon
authors.affiliation: Hospices Civils de Lyon, et Université de Lyon, Lyon, France ; Service de Neurologie Vasculaire, Hôpital Pierre Wertheimer, Lyon, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Mechtouff
authors.affiliation: Hospices Civils de Lyon, et Université de Lyon, Lyon, France ; Service de Neurologie Vasculaire, Hôpital Pierre Wertheimer, Lyon, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Derex
authors.affiliation: CIRI, International Center for Infectiology Research, Inserm, U1111, Ecole Normale Supérieure de Lyon, Université Lyon 1, CNRS, UMR5308 Lyon, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Walzer
authors.affiliation: Manchester Centre for Genomic Médecine Interne et Vasculaire of Human Development Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK.
authors.forename: Gillian I
authors.initials: GI
authors.lastname: Rice
authors.affiliation: Hospices Civils de Lyon, et Université de Lyon, Lyon, France ; Service de Médecine Interne et Vasculaire, Centre Hospitalier Lyon Sud, Lyon, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Durieu
authors.affiliation: Manchester Centre for Genomic Médecine Interne et Vasculaire of Human Development Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK ; INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris Descartes - Sorbonne Paris Cité University, Institut Imagine, Hôpital Necker, Paris, France ; Paris Descartes University, Paris, France ; Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, 3rd Floor, Room 309, 24 boulevard du Montparnasse, 75015 Paris, France.
authors.forename: Yanick J
authors.initials: YJ
authors.lastname: Crow
mesh_terms: D000243:Adenosine Deaminase / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D000361:Agammaglobulinemia / Q000097:blood / Q000235:genetics*; D000483:Alleles; D002648:Child; D055106:Genome-Wide Association Study; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D007372:Interferons / Q000097:blood; D008297:Male; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D018375:Neutrophil Activation / Q000235:genetics*; D009504:Neutrophils / Q000473:pathology*; D000076106:SAM Domain and HD Domain-Containing Protein 1; D016511:Severe Combined Immunodeficiency / Q000097:blood / Q000235:genetics*; D014657:Vasculitis / Q000097:blood / Q000235:genetics; D055815:Young Adult
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D007372:Interferons; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; C408373:ADA2 protein, human; D000243:Adenosine Deaminase; D020559:Monomeric GTP-Binding Proteins
keywords: ADA2; Adenosine deaminase; Aicardi-Goutières syndrome; CECR1; Neutrophil signature; SAMHD1; Type I interferon