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.

Type I interferon-mediated autoinflammation due to DNase II deficiency

Marcuzzi, Annalisa;Piscianz, Elisa;
2017

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.
2017
Rodero, Mathieu P.; Tesser, Alessandra; Bartok, Eva; Rice, Gillian I.; Della Mina, Erika; Depp, Marine; Beitz, Benoit; Bondet, Vincent; Cagnard, Nicolas; Duffy, Darragh; Dussiot, Michael; Frã©mond, Marie-Louise; Gattorno, Marco; Guillem, Flavia; Kitabayashi, Naoki; Porcheray, Fabrice; Rieux-Laucat, Frederic; Seabra, Luis; Uggenti, Carolina; Volpi, Stefano; Zeef, Leo A. H.; Alyanakian, Marie-Alexandra; Beltrand, Jacques; Bianco, Anna Monica; Boddaert, Nathalie; Brouzes, Chantal; Candon, Sophie; Caorsi, Roberta; Charbit, Marina; Fabre, Monique; Faletra, Flavio; Girard, Muriel; Harroche, Annie; Hartmann, Evelyn; Lasne, Dominique; Marcuzzi, Annalisa; Neven, Bã©nã©dicte; Nitschke, Patrick; Pascreau, Tiffany; Pastore, Serena; Picard, Capucine; Picco, Paolo; Piscianz, Elisa; Polak, Michel; Quartier, Pierre; Rabant, Marion; Stocco, Gabriele; Taddio, Andrea; Uettwiller, Florence; Valencic, Erica; Vozzi, Diego; Hartmann, Gunther; Barchet, Winfried; Hermine, Olivier; Bader-Meunier, Brigitte; Tommasini, Alberto; Crow, Yanick J.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/2411503
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