The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome and of other undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (also called MDA5) cause a spectrum of neuroimmunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer gain of function such that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling. Our results demonstrate that aberrant sensing of nucleic acids can cause immune upregulation.

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  1. 1.

    , , & Lethality of interferon preparations for newborn mice. Nature 258, 76–78 (1975).

  2. 2.

    et al. Progressive glomerulonephritis in mice treated with interferon preparations at birth. Nature 263, 420–422 (1976).

  3. 3.

    et al. Interferon-induced disease in mice and rats. Ann. NY Acad. Sci. 350, 12–20 (1980).

  4. 4.

    Type I interferonopathies: a novel set of inborn errors of immunity. Ann. NY Acad. Sci. 1238, 91–98 (2011).

  5. 5.

    et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus. Nat. Genet. 38, 917–920 (2006).

  6. 6.

    et al. Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection. Nat. Genet. 38, 910–916 (2006).

  7. 7.

    et al. Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response. Nat. Genet. 41, 829–832 (2009).

  8. 8.

    et al. Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature. Nat. Genet. 44, 1243–1248 (2012).

  9. 9.

    et al. Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study. Lancet Neurol. 12, 1159–1169 (2013).

  10. 10.

    et al. Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature. Nat. Genet. 43, 127–131 (2011).

  11. 11.

    , & Cytosolic sensing of viruses. Immunity 38, 855–869 (2013).

  12. 12.

    et al. Cooperative assembly and dynamic disassembly of MDA5 filaments for viral dsRNA recognition. Proc. Natl. Acad. Sci. USA 108, 21010–21015 (2011).

  13. 13.

    et al. Kinetic mechanism for viral dsRNA length discrimination by MDA5 filaments. Proc. Natl. Acad. Sci. USA 109, E3340–E3349 (2012).

  14. 14.

    et al. Structural basis for dsRNA recognition, filament formation, and antiviral signal activation by MDA5. Cell 152, 276–289 (2013).

  15. 15.

    et al. Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutières syndrome. Am. J. Hum. Genet. 80, 811–815 (2007).

  16. 16.

    et al. Dystonia, mental deterioration, and dyschromatosis symmetrica hereditaria in a family with ADAR1 mutation. Mov. Disord. 21, 1510–1513 (2006).

  17. 17.

    et al. A type I interferon signature identifies bilateral striatal necrosis due to mutations in ADAR1. J. Med. Genet. 51, 76–82 (2014).

  18. 18.

    et al. Dyschromatosis symmetrica hereditaria associated with neurological disorders. J. Dermatol. 35, 662–666 (2008).

  19. 19.

    et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J. Exp. Med. 197, 711–723 (2003).

  20. 20.

    et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc. Natl. Acad. Sci. USA 100, 2610–2615 (2003).

  21. 21.

    et al. Association of IFIH1 rs1990760 polymorphism with susceptibility to autoimmune diseases: a meta-analysis. Autoimmunity 46, 455–462 (2013).

  22. 22.

    , , & Ifih1 gene dose effect reveals MDA5-mediated chronic type I IFN gene signature, viral resistance, and accelerated autoimmunity. J. Immunol. 188, 1451–1459 (2012).

  23. 23.

    et al. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324, 387–389 (2009).

  24. 24.

    & Aicardi-Goutières syndrome and related phenotypes: linking nucleic acid metabolism with autoimmunity. Hum. Mol. Genet. 18, R130–R136 (2009).

  25. 25.

    Endogenous retroelements and autoimmune disease. Curr. Opin. Immunol. 24, 692–697 (2012).

  26. 26.

    et al. Identification of an LGP2-associated MDA5 agonist in picornavirus-infected cells. eLife 3, e01535 (2014).

  27. 27.

    et al. Autoimmune disorders associated with gain of function of the intracellular sensor MDA5. Immunity 40, 199–212 (2014).

  28. 28.

    et al. Therapies in Aicardi-Goutières syndrome. Clin. Exp. Immunol. 175, 1–8 (2014).

  29. 29.

    Enzyme Structure and Mechanism 2nd edn. (W H Freeman, New York, 1985).

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We sincerely thank the participating families for the use of genetic samples and clinical information and all clinicians who contributed samples and data not included in this manuscript. We thank D. Chase for proofreading the manuscript. We thank G. Notarangelo for helpful discussion. Y.d.T.D. holds a Novartis Foundation postdoctoral fellowship. S.H. holds a Pew scholarship and Career Development award from Boston Children's Hospital. Y.J.C. acknowledges the Manchester Biomedical Research Centre, Manchester Academic Health Sciences Centre, the Greater Manchester Comprehensive Local Research Network, the Great Ormond Street Hospital Children's Charity, the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement 241779 and the European Research Council (GA 309449). The authors would like to thank the NHLBI GO ESP and its ongoing studies, which 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).

Author information

Author notes

    • Gillian I Rice
    •  & Yoandris del Toro Duany

    These authors contributed equally to this work.

    • Sun Hur
    •  & Yanick J Crow

    These authors jointly directed this work.


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

    • Gillian I Rice
    • , Emma M Jenkinson
    • , Gabriella M A Forte
    • , Beverley H Anderson
    • , James O'Sullivan
    • , Simon G Williams
    •  & Yanick J Crow
  2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.

    • Yoandris del Toro Duany
    •  & Sun Hur
  3. Department of Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Yoandris del Toro Duany
    •  & Sun Hur
  4. Child Neurology and Psychiatry Unit, C. Mondino National Neurological Institute, Pavia, Italy.

    • Giada Ariaudo
    •  & Simona Orcesi
  5. Department of Brain and Behavioral Sciences, Unit of Child Neurology and Psychiatry, University of Pavia, Pavia, Italy.

    • Giada Ariaudo
  6. Department of Pediatric Immunology and Rheumatology, INSERM U768, Imagine Foundation, Assistance Publique–Hôpitaux de Paris (AP-HP), Hôpital Necker, Paris, France.

    • Brigitte Bader-Meunier
  7. Department of Paediatric Rheumatology, Alder Hey Children's National Health Service (NHS) Foundation Trust, Liverpool, UK.

    • Eileen M Baildam
    •  & Michael W Beresford
  8. Department of Developmental Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Stella Maris, Pisa, Italy.

    • Roberta Battini
    •  & Manuela Casarano
  9. Institute of Translational Medicine, University of Liverpool, Liverpool, UK.

    • Michael W Beresford
  10. Service de Pédiatrie 1, Centre Hospitalier Universitaire (CHU) de Dijon, Dijon, France.

    • Mondher Chouchane
  11. Department of Pediatrics, Azienda Ospedaliero Universitaria (AOU) Meyer and University of Florence, Florence, Italy.

    • Rolando Cimaz
  12. Division of Pediatric Neurology, Department of Pediatrics, University of Colorado School of Medicine, Denver, Colorado, USA.

    • Abigail E Collins
  13. Department of Paediatrics, Rainbow House NHS Ayrshire and Arran, Irvine, UK.

    • Nuno J V Cordeiro
  14. Neuroimmunology Group, Children's Hospital at Westmead, University of Sydney, Sydney, New South Wales, Australia.

    • Russell C Dale
  15. Department of Paediatric Rheumatology, Royal Hospital for Sick Children, Glasgow, UK.

    • Joyce E Davidson
  16. Department of Paediatric Neurology, University Hospitals Leuven, Leuven, Belgium.

    • Liesbeth De Waele
    •  & Lieven Lagae
  17. Department of Pediatric Neurology, INSERM U768, Imagine Foundation, AP-HP, Hôpital Necker, Paris, France.

    • Isabelle Desguerre
  18. Centre de Génétique, Hôpital d'Enfants, CHU de Dijon and Université de Bourgogne, Dijon, France.

    • Laurence Faivre
    •  & Alice Masurel-Paulet
  19. Child Neurology and Psychiatry Unit. Civil Hospital, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

    • Elisa Fazzi
  20. Service de Génétique Médicale, CHU de Nantes, Nantes, France.

    • Bertrand Isidor
  21. INSERM, UMRS 957, Nantes, France.

    • Bertrand Isidor
  22. Division of General Pediatrics, Department of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton, Ontario, Canada.

    • Andrew R Latchman
  23. Université et Faculté de Medecine Paris Descartes, Paris, France.

    • Pierre Lebon
  24. Department of Pediatrics, Clinical Genetics Program, McMaster Children's Hospital, McMaster University, Hamilton, Ontario, Canada.

    • Chumei Li
    •  & Marta Szybowska
  25. Department of Paediatric Neurology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.

    • John H Livingston
  26. Clinics Hospital of Ribeirao Preto, University of São Paulo, São Paulo, Brazil.

    • Charles M Lourenço
  27. Operative Unit Child Neuropsychiatry, Department of Neuroscience, Giannina Gaslini Institute, Genoa, Italy.

    • Maria Margherita Mancardi
  28. Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.

    • Iain B McInnes
  29. Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, University of Sydney, Sydney, New South Wales, Australia.

    • Manoj P Menezes
  30. Department of Genetics, Groupe Hospitalier Pitié Salpêtrière, AP-HP, Paris, France.

    • Cyril Mignot
  31. Paediatric Rheumatology, Giannina Gaslini Institute, Genoa, Italy.

    • Paolo P Picco
  32. Clinical Department of Pediatrics, San Paolo Hospital, University of Milan, Milan, Italy.

    • Enrica Riva
    •  & Elisabetta Salvatici
  33. Department of Neurology, Great Ormond Street Hospital for Children, London, UK.

    • Robert A Robinson
  34. Service de Neuropédiatrie, Centre de Référence de Neurogénétique, Hôpital A. Trousseau, AP-HP, Hôpitaux Universitaire Est Parisien (HUEP), Paris, France.

    • Diana Rodriguez
  35. Université Pierre et Marie Curie (UPMC), Université Paris 06, Paris, France.

    • Diana Rodriguez
  36. INSERM U676, Paris, France.

    • Diana Rodriguez
  37. Department of Paediatric Rheumatology, University of Cape Town, Red Cross War Memorial Children's Hospital, Cape Town, Republic of South Africa.

    • Christiaan Scott
    •  & Kate Webb
  38. Department of Clinical Genetics, Southern General Hospital, Glasgow, UK.

    • John L Tolmie
  39. Department of Pediatric Neurology, Children's National Medical Center, Washington, DC, USA.

    • Adeline Vanderver
  40. Service de Néonatalogie et Réanimation, Hôpital Charles Nicolle, CHU Rouen, Rouen, France.

    • Catherine Vanhulle
  41. Neurology Department. Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.

    • Jose Pedro Vieira
  42. Division of Pediatric Neurology, Department of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton, Ontario, Canada.

    • Robyn N Whitney
  43. US National Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, US National Institutes of Health, Bethesda, Maryland, USA.

    • Lynne A Wolfe
  44. Paediatric Neurosciences Research Group, Fraser of Allander Neurosciences Unit, Royal Hospital for Sick Children, Glasgow, UK.

    • Sameer M Zuberi
  45. School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

    • Sameer M Zuberi


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B.H.A., J.O. and S.G.W. performed exome sequencing. E.M.J., G.I.R. and Y.J.C. performed exome data analysis. G.I.R. performed quantitative PCR analysis and Sanger sequencing with assistance from E.M.J. and G.M.A.F. G.M.A.F. and B.H.A. performed genotyping analysis with assistance from G.I.R. Y.d.T.D. performed IFIH1 protein studies. S.H. performed modeling studies. Y.J.C. and S.H. designed and supervised the project and wrote the manuscript, with support from G.I.R. G.A., B.B.-M., E.M.B., R.B., M.W.B., M. Casarano, M. Chouchane, R.C., A.E.C., N.J.V.C., R.C.D., J.E.D., L.D.W., I.D., L.F., E.F., B.I., L.L., A.R.L., P.L., C.L., J.H.L., C.M.L., M.M.M., A.M.-P., I.B.M., M.P.M., C.M., S.O., P.P.P., E.R., R.A.R., D.R., E.S., C.S., M.S., J.L.T., A.V., C.V., J.P.V., K.W., R.N.W., L.A.W. and S.M.Z. identified affected individuals or assisted with related clinical and laboratory studies.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Sun Hur or Yanick J Crow.

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