Key Points
Multiorgan inflammation with IFN signature is observed in Adar1K948N/K948N mice.
White matter abnormalities and gliosis are detected in aged Adar1K948N/K948N mice.
A K948N point mutation reduces ADAR1 p150–mediated RNA editing, activating MDA5.
Abstract
Aicardi–Goutières syndrome (AGS) is a congenital inflammatory disorder accompanied by overactivated type I IFN signaling and encephalopathy with leukodystrophy and intracranial calcification. To date, none of the mouse models carrying an AGS-causative mutation has mimicked such brain pathology. Here, we established a mutant mouse model carrying a K948N point mutation, corresponding to an AGS-causative K999N mutation, located in a deaminase domain of the Adar1 gene that encodes an RNA editing enzyme. Adar1K948N/K948N mice displayed postnatal growth retardation. Hyperplasia of splenic white pulps with germinal centers and hepatic focal inflammation were observed from 2 mo of age. Inflammation developed in the lungs and heart with lymphocyte infiltration in an age-dependent manner. Furthermore, white matter abnormalities with astrocytosis and microgliosis were detected at 1 y of age. The increased expression of IFN-stimulated genes was detected in multiple organs, including the brain, from birth. In addition, single-nucleus RNA sequencing revealed that this elevated expression of IFN-stimulated genes was commonly observed in all neuronal subtypes, including neurons, oligodendrocytes, and astrocytes. We further showed that a K948N point mutation reduced the RNA editing activity of ADAR1 in vivo. The pathological abnormalities found in Adar1K948N/K948N mice were ameliorated by either the concurrent deletion of MDA5, a cytosolic sensor of unedited transcripts, or the sole expression of active ADAR1 p150, an isoform of ADAR1. Collectively, such data suggest that although the degree is mild, Adar1K948N/K948N mice mimic multiple AGS phenotypes, including encephalopathy, which is caused by reduced RNA editing activity of the ADAR1 p150 isoform.
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Footnotes
This work was supported by Grants-in-Aid for Scientific Research (KAKENHI) (20H03341 to Y. Kawahara, 18K15186 and 21K07080 to T.N., 20J11266 to J.I.K., and 18K11526 to Y. Kato) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan; by grants (JP20ek0109433 and JP21ek0109433 to T.N.) from the Japan Agency for Medical Research and Development; by grants from the Tokyo Biochemical Research Foundation (to Y. Kawahara) and the Naito Foundation, Novartis research grants, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, Astellas Foundation for Research on Metabolic Disorders, the Uehara Memorial Foundation, the Osaka Medical Research Foundation for Intractable Diseases (to T.N.); and by grants from the Takeda Science Foundation (to Y. Kawahara and T.N.). Y.X. was supported by MEXT scholarships. J.I.K. was supported by the Korean Scholarship Foundation and a Research Fellowship for Young Scientists from the Japan Society for the Promotion of Science.
M.I., T.N., and Y. Kawahara designed the study and wrote the manuscript. Y. Kato and R.Y. performed all the bioinformatics analyses. E.M. performed histological diagnoses. M.I., T.N., T.S., J.I.K., H.T., Y.X., and Y. Kawahara performed all other experiments. All authors agreed to the content of the final manuscript.
The online version of this article contains supplemental material.
Abbreviations used in this article
- ADAR
- adenosine deaminase acting on RNA
- AGS
- Aicardi–Goutières syndrome
- A-to-I
- adenosine to inosine
- CSF
- cerebrospinal fluid
- GFAP
- glial fibrillary acidic protein
- Iba1
- ionized calcium binding adapter protein 1
- ISG
- IFN-stimulated gene
- KI
- knock-in
- KO
- knockout
- MDA5
- melanoma differentiation–associated gene 5
- snRNA-seq
- single-nucleus RNA sequencing
- Received June 2, 2021.
- Accepted October 13, 2021.
- Copyright © 2021 by The American Association of Immunologists, Inc.
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