Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature

Abstract

Adenosine deaminases acting on RNA (ADARs) catalyze the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) and thereby potentially alter the information content and structure of cellular RNAs. Notably, although the overwhelming majority of such editing events occur in transcripts derived from Alu repeat elements, the biological function of non-coding RNA editing remains uncertain. Here, we show that mutations in ADAR1 (also known as ADAR) cause the autoimmune disorder Aicardi-Goutières syndrome (AGS). As in Adar1-null mice, the human disease state is associated with upregulation of interferon-stimulated genes, indicating a possible role for ADAR1 as a suppressor of type I interferon signaling. Considering recent insights derived from the study of other AGS-related proteins, we speculate that ADAR1 may limit the cytoplasmic accumulation of the dsRNA generated from genomic repetitive elements.

Editing of Cellular Self-RNAs by Adenosine Deaminase ADAR1 Suppresses Innate Immune Stress Responses

“…However, suppression of these dsRNA-dependent responses by ADAR1 remarkably was not observed with the measles C mutant (7,25,27), a mutant now understood to produce much higher amounts of viral dsRNA than either WT or the V mutant virus (23,27,64). Our results described herein, together with those of others (65)(66)(67), reveal that in the absence of ADAR1 at least some of the cytoplasmic sensors of dsRNA are also triggered by cellular (self) dsRNAs. Transcriptional profiling and pathway analyses carried out with mouse embryo cells revealed a strong association between ADAR1 catalytic deficiency and the gene expression signature of IFN-treated or virus-infected cells characteristic of RIG-I and MDA5 activation (65,68).…”

“…The conditional Adar1 mouse knock-out and the knock-in of a catalytically deficient E861A mutant ADAR1 both give rise to an IFN signature (65,68). Likewise, human Aicardi-Goutieres syndrome patients with mutations in ADAR1 show a type I IFN signature (66). These results, taken together, suggest that ADAR1 p150 catalytic activity and hence the generation of inosine in dsRNA lead to a suppression of the type 1 IFN response.…”

Ribonuclease H2 mutations induce a cGAS/STING‐dependent innate immune response

“…These comprise the RNASEH2A, RNASEH2B and RNASEH2C proteins of the RNase H2 endonuclease complex (Crow et al , 2006b) as well as TREX1, SAMHD1, ADAR and IFIH1 (Crow et al , 2006a; Rice et al , 2009, 2012, 2014). Heterozygous mutations in the three RNase H2 genes (Günther et al , 2015) and TREX1 (Lee‐Kirsch et al , 2007) are also associated with systemic lupus erythematosus.…”

ADAR1 is required for differentiation and neural induction by regulating microRNA processing in a catalytically independent manner

“…Moreover, hematopoietic lineage-specific ADAR1 knockout revealed that ADAR1 played an essential role in hematopoietic stem cell maintenance [25]; however, the detailed mechanism underlying embryonic lethality caused by ADAR1 deficiency has remained elusive. In addition, while ADAR1-deficient mice exhibited little aberrant neuronal phenotype prior to embryonic lethality [23,24], mutations in human ADAR1 gene were shown to be associated with Aicardi-Goutières syndrome [26], an early-onset encephalopathy that often results in severe and permanent neurological damage, indicating that ADAR1 may play an important role during neural development in humans.…”