Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature (original) (raw)

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Acknowledgements

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.

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Authors and Affiliations

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. Department of Neuroscience, Laboratory of Molecular Medicine, 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. Women and Children's Division, Section of Child Neurology, 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

Authors

1. Gillian I Rice
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2. Paul R Kasher
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3. Gabriella M A Forte
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4. Niamh M Mannion
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5. Sam M Greenwood
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6. Marcin Szynkiewicz
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7. Jonathan E Dickerson
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8. Sanjeev S Bhaskar
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9. Massimiliano Zampini
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10. Tracy A Briggs
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11. Emma M Jenkinson
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12. Carlos A Bacino
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13. Roberta Battini
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14. Enrico Bertini
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15. Paul A Brogan
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16. Louise A Brueton
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17. Marialuisa Carpanelli
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18. Corinne De Laet
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19. Pascale de Lonlay
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20. Mireia del Toro
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21. Isabelle Desguerre
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22. Elisa Fazzi
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23. Àngels Garcia-Cazorla
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24. Arvid Heiberg
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25. Masakazu Kawaguchi
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26. Ram Kumar
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27. Jean-Pierre S-M Lin
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28. Charles M Lourenco
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29. Alison M Male
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30. Wilson Marques Jr
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31. Cyril Mignot
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32. Ivana Olivieri
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33. Simona Orcesi
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34. Prab Prabhakar
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35. Magnhild Rasmussen
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36. Robert A Robinson
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37. Flore Rozenberg
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38. Johanna L Schmidt
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39. Katharina Steindl
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40. Tiong Y Tan
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41. William G van der Merwe
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42. Adeline Vanderver
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43. Grace Vassallo
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44. Emma L Wakeling
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45. Evangeline Wassmer
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46. Elizabeth Whittaker
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47. John H Livingston
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48. Pierre Lebon
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49. Tamio Suzuki
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50. Paul J McLaughlin
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51. Liam P Keegan
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52. Mary A O'Connell
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53. Simon C Lovell
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54. Yanick J Crow
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Contributions

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.

Corresponding author

Correspondence toYanick J Crow.

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Rice, G., Kasher, P., Forte, G. et al. Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature.Nat Genet 44, 1243–1248 (2012). https://doi.org/10.1038/ng.2414

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• Received: 22 March 2012
• Accepted: 29 August 2012
• Published: 23 September 2012
• Issue Date: November 2012
• DOI: https://doi.org/10.1038/ng.2414