1. RNase H2 catalytic core Aicardi-Goutières syndrome–related mutant invokes cGAS–STING innate immune-sensing pathway in mice
- Author
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Hyongi Chon, H. Douglas Morris, Robert J. Crouch, Susana M. Cerritelli, Jerrold M. Ward, Vladislav Pokatayev, Kiran Sakhuja, Nan Yan, and Naushaba Hasin
- Subjects
Male ,0301 basic medicine ,RNase P ,Ribonuclease H ,Immunology ,Mutant ,Nervous System Malformations ,medicine.disease_cause ,Mice ,03 medical and health sciences ,Autoimmune Diseases of the Nervous System ,Interferon ,Catalytic Domain ,medicine ,Animals ,Humans ,Immunology and Allergy ,RNase H ,Research Articles ,Cells, Cultured ,Crosses, Genetic ,RNASEH2A ,Mutation ,Innate immune system ,biology ,Homozygote ,Brief Definitive Report ,Membrane Proteins ,Fibroblasts ,Embryo, Mammalian ,medicine.disease ,Nucleotidyltransferases ,Molecular biology ,eye diseases ,Immunity, Innate ,3. Good health ,HEK293 Cells ,Long Interspersed Nucleotide Elements ,Phenotype ,030104 developmental biology ,Gene Expression Regulation ,biology.protein ,Aicardi–Goutières syndrome ,Female ,Interferons ,Signal Transduction ,medicine.drug - Abstract
Mice with a mutated form of RNase H2 found in patients with the neuroinflammatory Aicardi-Goutières Syndrome develop a lethal, cGAS–STING–dependent disease., The neuroinflammatory autoimmune disease Aicardi-Goutières 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, Rnaseh2aG37S/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 RNASEH2-associated autoimmune diseases.
- Published
- 2016