| First Author | Nakahama T | Year | 2021 |
| Journal | Immunity | Volume | 54 |
| Issue | 9 | Pages | 1976-1988.e7 |
| PubMed ID | 34525338 | Mgi Jnum | J:323650 |
| Mgi Id | MGI:6856558 | Doi | 10.1016/j.immuni.2021.08.022 |
| Citation | Nakahama T, et al. (2021) Mutations in the adenosine deaminase ADAR1 that prevent endogenous Z-RNA binding induce Aicardi-Goutieres-syndrome-like encephalopathy. Immunity 54(9):1976-1988.e7 |
| abstractText | Mutations in the adenosine-to-inosine RNA-editing enzyme ADAR1 p150, including point mutations in the Z-RNA recognition domain Zalpha, are associated with Aicardi-Goutieres syndrome (AGS). Here, we examined the in vivo relevance of ADAR1 binding of Z-RNA. Mutation of W197 in Zalpha, which abolished Z-RNA binding, reduced RNA editing. Adar1(W197A/W197A) mice displayed severe growth retardation after birth, broad expression of interferon-stimulated genes (ISGs), and abnormal development of multiple organs. Notably, malformation of the brain was accompanied by white matter vacuolation and gliosis, reminiscent of AGS-associated encephalopathy. Concurrent deletion of the double-stranded RNA sensor MDA5 ameliorated these abnormalities. ADAR1 (W197A) expression increased in a feedback manner downstream of type I interferons, resulting in increased RNA editing at a subset of, but not all, ADAR1 target sites. This increased expression did not ameliorate inflammation in Adar1(W197A/W197A) mice. Thus, editing of select endogenous RNAs by ADAR1 is essential for preventing inappropriate MDA5-mediated inflammation, with relevance to the pathogenesis of AGS. |
