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.
Original language | English |
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Article number | 2176 |
Journal | Nature Communications |
Volume | 8 |
Issue number | 1 |
DOIs | |
Publication status | Published - 19 Dec 2017 |
Keywords / Materials (for Non-textual outputs)
- Adolescent
- Antiviral Agents/pharmacology
- Child
- Deoxyribonucleases/deficiency
- Endodeoxyribonucleases/deficiency
- Erythroblasts/immunology
- Female
- Gene Expression Profiling
- Hematopoiesis/immunology
- Hereditary Autoinflammatory Diseases/blood
- Humans
- Interferon-alpha/blood
- Male
- Mutation
- Phosphorylation
- 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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Yanick Crow
- Deanery of Molecular, Genetic and Population Health Sciences - Chair of Genomic Medicine
- Centre for Genomic and Experimental Medicine
- Edinburgh Neuroscience
Person: Academic: Research Active