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Nat Genet. 2014 May;46(5):503-9. doi: 10.1038/ng.2933. Epub 2014 Mar 30.

Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling.

Author information

  • 11] Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, UK. [2].
  • 21] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Medicine, Boston Children's Hospital, Boston, Massachusetts, USA. [3].
  • 3Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, UK.
  • 41] Child Neurology and Psychiatry Unit, C. Mondino National Neurological Institute, Pavia, Italy. [2] Department of Brain and Behavioral Sciences, Unit of Child Neurology and Psychiatry, University of Pavia, Pavia, Italy.
  • 5Department of Pediatric Immunology and Rheumatology, INSERM U768, Imagine Foundation, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker, Paris, France.
  • 6Department of Paediatric Rheumatology, Alder Hey Children's National Health Service (NHS) Foundation Trust, Liverpool, UK.
  • 7Department of Developmental Neuroscience, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Stella Maris, Pisa, Italy.
  • 81] Department of Paediatric Rheumatology, Alder Hey Children's National Health Service (NHS) Foundation Trust, Liverpool, UK. [2] Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
  • 9Service de Pédiatrie 1, Centre Hospitalier Universitaire (CHU) de Dijon, Dijon, France.
  • 10Department of Pediatrics, Azienda Ospedaliero Universitaria (AOU) Meyer and University of Florence, Florence, Italy.
  • 11Division of Pediatric Neurology, Department of Pediatrics, University of Colorado School of Medicine, Denver, Colorado, USA.
  • 12Department of Paediatrics, Rainbow House NHS Ayrshire and Arran, Irvine, UK.
  • 13Neuroimmunology Group, Children's Hospital at Westmead, University of Sydney, Sydney, New South Wales, Australia.
  • 14Department of Paediatric Rheumatology, Royal Hospital for Sick Children, Glasgow, UK.
  • 15Department of Paediatric Neurology, University Hospitals Leuven, Leuven, Belgium.
  • 16Department of Pediatric Neurology, INSERM U768, Imagine Foundation, AP-HP, Hôpital Necker, Paris, France.
  • 17Centre de Génétique, Hôpital d'Enfants, CHU de Dijon and Université de Bourgogne, Dijon, France.
  • 18Child Neurology and Psychiatry Unit. Civil Hospital, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
  • 191] Service de Génétique Médicale, CHU de Nantes, Nantes, France. [2] INSERM, UMRS 957, Nantes, France.
  • 20Division of General Pediatrics, Department of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton, Ontario, Canada.
  • 21Université et Faculté de Medecine Paris Descartes, Paris, France.
  • 22Department of Pediatrics, Clinical Genetics Program, McMaster Children's Hospital, McMaster University, Hamilton, Ontario, Canada.
  • 23Department of Paediatric Neurology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
  • 24Clinics Hospital of Ribeirao Preto, University of São Paulo, São Paulo, Brazil.
  • 25Operative Unit Child Neuropsychiatry, Department of Neuroscience, Giannina Gaslini Institute, Genoa, Italy.
  • 26Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
  • 27Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, University of Sydney, Sydney, New South Wales, Australia.
  • 28Department of Genetics, Groupe Hospitalier Pitié Salpêtrière, AP-HP, Paris, France.
  • 29Child Neurology and Psychiatry Unit, C. Mondino National Neurological Institute, Pavia, Italy.
  • 30Paediatric Rheumatology, Giannina Gaslini Institute, Genoa, Italy.
  • 31Clinical Department of Pediatrics, San Paolo Hospital, University of Milan, Milan, Italy.
  • 32Department of Neurology, Great Ormond Street Hospital for Children, London, UK.
  • 331] Service de Neuropédiatrie, Centre de Référence de Neurogénétique, Hôpital A. Trousseau, AP-HP, Hôpitaux Universitaire Est Parisien (HUEP), Paris, France. [2] Université Pierre et Marie Curie (UPMC), Université Paris 06, Paris, France. [3] INSERM U676, Paris, France.
  • 34Department of Paediatric Rheumatology, University of Cape Town, Red Cross War Memorial Children's Hospital, Cape Town, Republic of South Africa.
  • 35Department of Clinical Genetics, Southern General Hospital, Glasgow, UK.
  • 36Department of Pediatric Neurology, Children's National Medical Center, Washington, DC, USA.
  • 37Service de Néonatalogie et Réanimation, Hôpital Charles Nicolle, CHU Rouen, Rouen, France.
  • 38Neurology Department. Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.
  • 39Division of Pediatric Neurology, Department of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton, Ontario, Canada.
  • 40US National Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, US National Institutes of Health, Bethesda, Maryland, USA.
  • 411] Paediatric Neurosciences Research Group, Fraser of Allander Neurosciences Unit, Royal Hospital for Sick Children, Glasgow, UK. [2] School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

Abstract

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.

PMID:
24686847
[PubMed - indexed for MEDLINE]
PMCID:
PMC4004585
Free PMC Article
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