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PMID: 23001123 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature genetics ·Vol. 44 ·No. 11 ·2012-11-00 ·Pages 1243-8

Rice GI, Kasher PR, Forte GM, Mannion NM, Greenwood SM, Szynkiewicz M, Dickerson JE, Bhaskar SS, Zampini M, Briggs TA, Jenkinson EM, Bacino CA, Battini R, Bertini E, Brogan PA, Brueton LA, Carpanelli M, De Laet C, de Lonlay P, del Toro M, Desguerre I, Fazzi E, Garcia-Cazorla A, Heiberg A, Kawaguchi M, Kumar R, Lin JP, Lourenco CM, Male AM, Marques W, Mignot C, Olivieri I, Orcesi S, Prabhakar P, Rasmussen M, Robinson RA, Rozenberg F, Schmidt JL, Steindl K, Tan TY, van der Merwe WG, Vanderver A, Vassallo G, Wakeling EL, Wassmer E, Whittaker E, Livingston JH, Lebon P, Suzuki T, McLaughlin PJ, Keegan LP, O'Connell MA, Lovell SC, Crow YJ

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.

MeSH Terms
Adenosine Deaminase/genetics Alu Elements/genetics Animals Autoimmune Diseases of the Nervous System/genetics Exome Gene Expression Humans Interferon Type I/genetics,metabolism Mice Mutation Nervous System Malformations/genetics Protein Conformation RNA, Double-Stranded/genetics,metabolism RNA-Binding Proteins Sequence Analysis, DNA Signal Transduction Structure-Activity Relationship
Chemicals
Interferon Type I RNA, Double-Stranded RNA-Binding Proteins ADARB1 protein, human Adenosine Deaminase
Authors & Affiliations
54 authors, click to expand affiliations / ORCID
Rice Gillian I
Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, UK.
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 Angels
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
Supplementary Concepts
Aicardi-Goutieres syndrome (Disease)
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.2414
Published
2012-11-00
Epub
2012-00-23
Pages
1243-8
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC4154508
Subset
IM
Grants
NHLBI NIH HHS · RC2 HL102926 · United States
NHLBI NIH HHS · RC2 HL102924 · United States
NHLBI NIH HHS · HL-102926 · United States
NHLBI NIH HHS · HL-102925 · United States
NHLBI NIH HHS · RC2 HL103010 · United States
NHLBI NIH HHS · HL-102923 · United States
NHLBI NIH HHS · RC2 HL102923 · United States
NHLBI NIH HHS · UC2 HL102926 · United States
NHLBI NIH HHS · UC2 HL103010 · United States
NHLBI NIH HHS · HL-103010 · United States
NINDS NIH HHS · K08 NS060695 · United States
NHLBI NIH HHS · HL-102924 · United States
NHLBI NIH HHS · UC2 HL102923 · United States
NHLBI NIH HHS · UC2 HL102924 · United States
NHLBI NIH HHS · RC2 HL102925 · United States
NHLBI NIH HHS · UC2 HL102925 · United States
External Links
PubMed source DOI: 10.1038/ng.2414 PMC Full Text View journal details
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