title: RNase H2 catalytic core Aicardi-Goutières syndrome-related mutant invokes cGAS-STING innate immune-sensing pathway in mice.
abstract: 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, 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 RNASEH2-associated autoimmune diseases.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390 Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Vladislav
authors.initials: V
authors.lastname: Pokatayev
authors.affiliation: Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892.
authors.forename: Naushaba
authors.initials: N
authors.lastname: Hasin
authors.affiliation: Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892.
authors.forename: Hyongi
authors.initials: H
authors.lastname: Chon
authors.affiliation: Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892.
authors.forename: Susana M
authors.initials: SM
authors.lastname: Cerritelli
authors.affiliation: Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892.
authors.forename: Kiran
authors.initials: K
authors.lastname: Sakhuja
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892.
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Ward
authors.affiliation: NIH Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 21042.
authors.forename: H Douglas
authors.initials: HD
authors.lastname: Morris
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390 Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Nan
authors.initials: N
authors.lastname: Yan
authors.affiliation: Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892 crouchr@helix.nih.gov.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Crouch
mesh_terms: D000818:Animals; D020274:Autoimmune Diseases of the Nervous System / Q000235:genetics / Q000276:immunology*; D020134:Catalytic Domain; D002478:Cells, Cultured; D003433:Crosses, Genetic; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006720:Homozygote; D006801:Humans; D007113:Immunity, Innate; D007372:Interferons / Q000378:metabolism; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009421:Nervous System Malformations / Q000235:genetics / Q000276:immunology*; D009713:Nucleotidyltransferases / Q000378:metabolism*; D010641:Phenotype; D016914:Ribonuclease H / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D007372:Interferons; D008565:Membrane Proteins; D009713:Nucleotidyltransferases; D016914:Ribonuclease H; C530855:Sting1 protein, mouse; D000099197:STING Protein; C578391:cGAS protein, mouse; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase