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.
- Antiviral Agents/pharmacology
- Gene Expression Profiling
- Hereditary Autoinflammatory Diseases/blood
- RNA, Messenger/analysis
- STAT1 Transcription Factor/metabolism
- STAT3 Transcription Factor/metabolism
- Sequence Analysis, RNA
- Signal Transduction/immunology
- Up-Regulation/drug effects
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- Deanery of Molecular, Genetic and Population Health Sciences - Chair of Genomic Medicine
- Centre for Genomic and Experimental Medicine
- Edinburgh Neuroscience
Person: Academic: Research Active