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Type I interferon-mediated autoinflammation due to DNase II deficiency

Mathieu Rodéro 1 Alessandra Tesser 2 Eva Bartok 3 Gillian Rice 4 Erika Della Mina Marine Depp Benoit Beitz 5 Vincent Bondet 6 Nicolas Cagnard 7 Darragh Duffy 6 Michael Dussiot 8 Marie-Louise Frémond Marco Gattorno 9 Flavia Guillem 8 Naoki Kitabayashi 8 Fabrice Porcheray 5 Frederic Rieux-Laucat 8 Luis Seabra Carolina Uggenti Stefano Volpi 10 Leo Zeef 11 Marie-Alexandra Alyanakian 12 Jacques Beltrand 8 Anna Monica Bianco 13 Nathalie Boddaert 14 Chantal Brouzes 15 Sophie Candon Roberta Caorsi Marina Charbit 16 Monique Fabre 17 Flavio Faletra Muriel Girard Annie Harroche Evelyn Hartmann Dominique Lasne 15 Annalisa Marcuzzi Bénédicte Neven 12 Patrick Nitschke 18 Tiffany Pascreau Serena Pastore Capucine Picard 19 Paolo Picco Elisa Piscianz Michel Polak 20 Pierre Quartier 12 Marion Rabant 21 Gabriele Stocco 22 Andrea Taddio Florence Uettwiller Erica Valencic Diego Vozzi Gunther Hartmann 23 Winfried Barchet Olivier Hermine 24 Brigitte Bader-Meunier 12 Alberto Tommasini 25 Yanick Crow 4, 1
1 Equipe Inserm U1163 - Laboratory of neurogenetics and neuroinflammation
IMAGINE - U1163 - Imagine - Institut des maladies génétiques
2 University of Trieste
3 University of Bonn
4 Academic Unit of Medical Genetic
5 Microbiology Technology Institute,
6 Immunobiologie des Cellules dendritiques
7 SFR Necker - UMS 3633 / US24 - Structure Fédérative de Recherche Necker
8 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
9 Giannina Gaslini Institute
10 Istituto Giannina Gaslini, Genova
11 University of Manchester [Manchester]
12 Service d'immuno-hématologie pédiatrique [CHU Necker]
13 University of Trieste
14 Service de Radiologie et imagerie médicale [CHU Necker]
15 ERL 8254 - Equipe Inserm U1163 - Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications
IMAGINE - U1163 - Imagine - Institut des maladies génétiques : ERL8254
16 Service de néphrologie pédiatrique [CHU Necker]
17 Hôpital Bicêtre
18 BIP-D - Plate Forme Paris Descartes de Bioinformatique
19 Centre d'étude des Déficits Immunitaires
20 Service d'endocrinologie, gynécologie et diabétologie pédiatriques [CHU Necker]
21 CHU Necker - Enfants Malades [AP-HP]
22 Department of Life Sciences
23 Institute of Clinical Chemistry and Pharmacology, Center for Integrated Oncology
24 Service d'Hématologie Adulte
25 IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, Italy
Abstract : Microbial nucleic acid recognition serves as the major stimulus to an antiviral response, implying a requirement to limit the misrepresentation of self nucleic acids as non-self and the induction of autoinflammation. By systematic screening using a panel of interferon-stimulated genes we identify two siblings and a singleton variably demonstrating severe neonatal anemia, membranoproliferative glomerulonephritis, liver fibrosis, deforming arthropathy and increased anti-DNA antibodies. In both families we identify biallelic mutations in DNASE2, associated with a loss of DNase II endonuclease activity. We record increased interferon alpha protein levels using digital ELISA, enhanced interferon signaling by RNA-Seq analysis and constitutive upregulation of phosphorylated STAT1 and STAT3 in patient lymphocytes and monocytes. A hematological disease transcriptomic signature and increased numbers of erythroblasts are recorded in patient peripheral blood, suggesting that interferon might have a particular effect on hematopoiesis. These data define a type I interferonopathy due to DNase II deficiency in humans.
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PASTEUR | CNRS | UNIV-PARIS5 | USPC | UNIV-PARIS | UP-SANTE | INSERM

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Mathieu Rodéro, Alessandra Tesser, Eva Bartok, Gillian Rice, Erika Della Mina, et al.. Type I interferon-mediated autoinflammation due to DNase II deficiency. Nature Communications, Nature Publishing Group, 2017, 8 (1), pp.2176. ⟨10.1038/s41467-017-01932-3⟩. ⟨pasteur-01768950⟩

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