期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 213, 期 3, 页码 329-336出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20151464
关键词
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资金
- National Institutes of Health [AI098569, AR067135]
- Alliance for Lupus Research [329774]
- UT Southwestern Immunology graduate program training grant [2T32AI005284]
- Intramural Research Program of the National Institutes of Health
The neuroinflammatory autoimmune disease Aicardi-Goutieres syndrome (AGS) develops from mutations in genes encoding several nucleotide-processing proteins, including RNase H2. Defective RNase H2 may induce accumulation of self-nucleic acid species that trigger chronic type I interferon and inflammatory responses, leading to AGS pathology. We created a knock-in mouse model with an RNase H2 AGS mutation in a highly conserved residue of the catalytic subunit, Rnaseh2a(G37S/G37S) (G37S), to understand disease pathology. G37S homozygotes are perinatal lethal, in contrast to the early embryonic lethality previously reported for Rnaseh2b- or Rnaseh2c-null mice. Importantly, we found that the G37S mutation led to increased expression of interferon-stimulated genes dependent on the cGAS-STING signaling pathway. Ablation of STING in the G37S mice results in partial rescue of the perinatal lethality, with viable mice exhibiting white spotting on their ventral surface. We believe that the G37S knock-in mouse provides an excellent animal model for studying RNA SEH2-associated autoimmune diseases.
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