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

• Published in: Nature genetics Vol. 44; no. 11; pp. 1243 - 1248
• Main Authors: Rice, Gillian I, Kasher, Paul R, Forte, Gabriella M A, Mannion, Niamh M, Greenwood, Sam M, Szynkiewicz, Marcin, Dickerson, Jonathan E, Bhaskar, Sanjeev S, Zampini, Massimiliano, Briggs, Tracy A, Jenkinson, Emma M, Bacino, Carlos A, Battini, Roberta, Bertini, Enrico, Brogan, Paul A, Brueton, Louise A, Carpanelli, Marialuisa, De Laet, Corinne, de Lonlay, Pascale, del Toro, Mireia, Desguerre, Isabelle, Fazzi, Elisa, Garcia-Cazorla, Àngels, Heiberg, Arvid, Kawaguchi, Masakazu, Kumar, Ram, Lin, Jean-Pierre S-M, Lourenco, Charles M, Male, Alison M, Marques, Wilson, Mignot, Cyril, Olivieri, Ivana, Orcesi, Simona, Prabhakar, Prab, Rasmussen, Magnhild, Robinson, Robert A, Rozenberg, Flore, Schmidt, Johanna L, Steindl, Katharina, Tan, Tiong Y, van der Merwe, William G, Vanderver, Adeline, Vassallo, Grace, Wakeling, Emma L, Wassmer, Evangeline, Whittaker, Elizabeth, Livingston, John H, Lebon, Pierre, Suzuki, Tamio, McLaughlin, Paul J, Keegan, Liam P, O'Connell, Mary A, Lovell, Simon C, Crow, Yanick J
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2012; Nature Publishing Group
• Subjects: 631/208/2489/144; 631/208/737; 631/250/249/1313; Adenosine deaminase; Adenosine Deaminase - genetics; Agriculture; Aicardi syndrome; Alu Elements - genetics; Animal Genetics and Genomics; Animals; Autoimmune Diseases of the Nervous System - genetics; Biological and medical sciences; Biomedicine; Cancer Research; Exome; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene Function; Gene mutations; Genetic aspects; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Health aspects; Human Genetics; Humans; Interferon; Interferon Type I - genetics; Interferon Type I - metabolism; letter; Malformations of the nervous system; Medical research; Medical sciences; Mice; Mutation; Nervous System Malformations - genetics; Neurology; Physiological aspects; Protein Conformation; Proteins; Risk factors; RNA; RNA, Double-Stranded - genetics; RNA, Double-Stranded - metabolism; RNA-Binding Proteins; Sequence Analysis, DNA; Signal Transduction; Structure-Activity Relationship; United States; Italy; United Kingdom; Eye disease; Nervous system diseases; Malformation; Aicardi syndrome; Central nervous system disease; Mutation; Congenital disease; Cerebral disorder
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.2414

Yanick Crow and colleagues show that mutations in ADAR1 cause the autoimmune disorder Aicardi-Goutières syndrome, accompanied by upregulation of interferon-stimulated genes. ADAR1 encodes an enzyme that catalyzes the deamination of adeonosine to inosine in double-stranded RNA, and the findings suggest a possible role for RNA editing in limiting the accumulation of repeat-derived RNA species. 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.