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.

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We sincerely thank the participating families for the use of genetic samples and clinical information. We thank B. Hamel, H. Brunner and other clinical collaborators for contributing samples not included in the current manuscript, A.P. Jackson for highlighting the presence of intracranial calcification in individuals with DSH with a p.Gly1007Arg alteration in ADAR1 and D.B. Stetson and D.T. Bonthron for critical reading of the manuscript. D.B. Stetson (University of Washington) provided the ADAR1 constructs used in the editing assays. We thank the NHLBI GO Exome Sequencing Project and its ongoing studies that produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the Women's Health Initiative (WHI) Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010). Y.J.C. acknowledges the Manchester National Institute for Health Research (NIHR) Biomedical Research Centre. The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement 241779 and from the Great Ormond Street Hospital Children's Charity.

Author information


  1. Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, UK.

    • Gillian I Rice
    • , Paul R Kasher
    • , Gabriella M A Forte
    • , Marcin Szynkiewicz
    • , Jonathan E Dickerson
    • , Sanjeev S Bhaskar
    • , Massimiliano Zampini
    • , Tracy A Briggs
    • , Emma M Jenkinson
    •  & Yanick J Crow
  2. Medical Research Council (MRC) Human Genetics Unit, Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Edinburgh, UK.

    • Niamh M Mannion
    • , Sam M Greenwood
    • , Liam P Keegan
    •  & Mary A O'Connell
  3. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

    • Carlos A Bacino
  4. Department of Developmental Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Stella Maris, Pisa, Italy.

    • Roberta Battini
  5. Laboratory of Molecular Medicine, Department of Neuroscience, Bambino Gesù Children's Research Hospital, Rome, Italy.

    • Enrico Bertini
  6. University College London (UCL) Institute of Child Health, London, UK.

    • Paul A Brogan
  7. Birmingham Women's National Health Service (NHS) Foundation Trust, Birmingham, UK.

    • Louise A Brueton
  8. Department of Child Neurology and Psychiatry, A Manzoni Hospital, Lecco, Italy.

    • Marialuisa Carpanelli
  9. Nutrition and Metabolism Unit, Hôpital Universitaire des Enfants Reine Fabiola (ULB), Brussels, Belgium.

    • Corinne De Laet
  10. Reference Center of Metabolic Diseases, Hôpital Necker–Enfants Malades, Paris Descartes University, Paris, France.

    • Pascale de Lonlay
  11. Pediatric Neurology Unit, Hospital Vall d'Hebron, Barcelona, Spain.

    • Mireia del Toro
  12. Neuropediatric Unit, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris V Descartes University, Necker Hospital, Paris, France.

    • Isabelle Desguerre
  13. Mother and Child Department, Unit of Child Neurology and Psychiatry, Civil Hospital, University of Brescia, Brescia, Italy.

    • Elisa Fazzi
  14. Department of Neurology, Hospital Sant Joan de Déu (HSJD), Barcelona, Spain.

    • Àngels Garcia-Cazorla
  15. El Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), Instituto de Salud Carlos III, Madrid, Spain.

    • Àngels Garcia-Cazorla
  16. Department of Medical Genetics, Oslo University Hospital, National Hospital, Oslo, Norway.

    • Arvid Heiberg
  17. Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, Japan.

    • Masakazu Kawaguchi
    •  & Tamio Suzuki
  18. Department of Neurology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.

    • Ram Kumar
  19. General Neurology & Complex Motor Disorders Service, Evelina Children's Hospital, Guy's & St. Thomas' NHS Foundation Trust, London, UK.

    • Jean-Pierre S-M Lin
  20. Department of Neurosciences and Behavior Sciences, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.

    • Charles M Lourenco
    •  & Wilson Marques Jr
  21. North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children, London, UK.

    • Alison M Male
  22. Département de Génétique et Cytogénétique, AP-HP, Groupe Hospitalier Pitié–Salpêtrière, Paris, France.

    • Cyril Mignot
  23. Service de Neuropédiatrie, AP-HP, Hopital Armand Trousseau, Paris, France.

    • Cyril Mignot
  24. Centre de Déficience des Déficiences Intellectuelles de Causes Rares, Paris, France.

    • Cyril Mignot
  25. Child Neurology and Psychiatry Unit, IRCCS C Mondino National Institute of Neurology Foundation, Pavia, Italy.

    • Ivana Olivieri
    •  & Simona Orcesi
  26. Department of Neurology, Great Ormond Street Hospital, London, UK.

    • Prab Prabhakar
    •  & Robert A Robinson
  27. Section of Child Neurology, Women and Children's Division, Oslo University Hospital, Oslo, Norway.

    • Magnhild Rasmussen
  28. Service de Virologie, Paris Descartes University, AP-HP, Hopital Cochin St. Vincent de Paul, Paris, France.

    • Flore Rozenberg
    •  & Pierre Lebon
  29. Department of Neurology, Children's National Medical Center, Washington, DC, USA.

    • Johanna L Schmidt
    •  & Adeline Vanderver
  30. Institute of Medical Genetics, University of Zurich, Schwerzenbach, Switzerland.

    • Katharina Steindl
  31. Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.

    • Tiong Y Tan
  32. Paediatric Department, Nobles Hospital, Strang, UK.

    • William G van der Merwe
  33. Neurology Department, Royal Manchester Children's Hospital, Manchester, UK.

    • Grace Vassallo
  34. North West Thames Regional Genetics Service, North West London Hospitals NHS Trust, Harrow, UK.

    • Emma L Wakeling
  35. Neurology Department, Birmingham Children's Hospital, Birmingham, UK.

    • Evangeline Wassmer
  36. Academic Department of Paediatrics, Imperial College London, London, UK.

    • Elizabeth Whittaker
  37. Department of Paediatric Neurology, Leeds General Infirmary, Leeds, UK.

    • John H Livingston
  38. Institute of Structural and Molecular Biology, School of Biological Sciences, The University of Edinburgh, Edinburgh, UK.

    • Paul J McLaughlin
  39. Faculty of Life Sciences, University of Manchester, Manchester, UK.

    • Simon C Lovell


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G.I.R. performed quantitative PCR analysis. P.R.K. performed protein blot analysis. G.M.A.F. performed cell culture and interferon stimulation experiments with assistance from G.I.R. and T.A.B. M.S. performed Sanger sequencing with assistance from M.Z., G.M.A.F. and E.M.J. G.I.R. analyzed sequence data. M.S. and G.M.A.F. undertook microsatellite genotyping. J.E.D. and S.S.B. undertook analysis of the exome sequence data. J.H.L. was responsible for neuroradiological phenotyping. P.L. and F.R. measured interferon activity in affected individuals. M.A.O., L.P.K., S.M.G. and N.M.M. carried out ADAR1 editing assays. T.S. and M.K. provided the DSH RNA samples. S.C.L. and P.J.M. carried out ADAR1 structural analysis. Y.J.C. designed and supervised the project and wrote the manuscript with support from G.I.R. C.A.B., R.B., E.B., P.A.B., L.A.B., M.C., C.D.L., P.d.L., M.d.T., I.D., E.F., A.G.-C., A.H., R.K., J.-P.S.-M.L., C.M.L., A.M.M., W.M., C.M., I.O., S.O., P.P., M.R., R.A.R., J.L.S., K.S., T.Y.T., W.G.v.d.M., A.V., G.V., E.L.W., E. Wassmer and E. Whittaker identified subjects with AGS or assisted with related clinical and laboratory studies.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Yanick J Crow.

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