Type I interferon mediated autoinflammation due to DNase II deficiency

Microbial nucleic acid recognition serves as the major stimulus to an antiviral response, implying a requirement to limit the misrepresentationof self nucleic acids as non-self and the induction of autoinflammation. By systematic screening using a panel of interferon-stimulated geneswe identify two siblings and a singleton variablydemonstrating severe neonatal anemia, membranoproliferative glomerulonephritis, liver fibrosis, deforming arthropathyand 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 interferonalpha protein levels using digital ELISA, enhanced interferonsignaling by RNA-Seqanalysis and constitutive upregulation of phosphorylated STAT1and STAT3 in patient lymphocytes and monocytes. A hematological diseasetranscriptomic signature and increased numbers of erythroblastsare recorded in patient peripheral blood, suggesting that interferonmight have a particular effect on hematopoiesis. These data define a type I interferonopathy due to DNase II deficiency in humans.