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Nat Genet. 2014 May;46(5):503-509. 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

1
Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, UK.
2
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
3
Boston Children's Hospital, Boston, MA 02115, USA.
4
Child Neurology and Psychiatry Unit, C. Mondino National Neurological Institute, Pavia, Italy.
5
Department of Brain and Behavioral Sciences, Unit of Child Neurology and Psychiatry, University of Pavia, Pavia, Italy.
6
Department of pediatric Immunology and Rheumatology, INSERM U 768, Imagine Foundation, APHP, Hôpital Necker, Paris, France.
7
Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.
8
Department of Developmental Neuroscience, IRCCS Stella Maris, Pisa, Italy.
9
Institute of Translational Medicine, University of Liverpool; Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.
10
Service de Pédiatrie 1, CHU de Dijon, Dijon, France.
11
AOU Meyer and University of Florence, Italy.
12
Department of Pediatrics, Division of Pediatric Neurology, University of Colorado, Denver, School of Medicine, USA.
13
Department of Paediatrics, Rainbow House NHS Ayrshire & Arran, Scotland, UK.
14
Neuroimmunology group, the Children's Hospital at Westmead, University of Sydney, Australia.
15
Department of Paediatric Rheumatology, Royal Hospital for Sick Children, Glasgow, UK.
16
Department of Development and Regeneration, KU Leuven, Paediatric Neurology, University Hospitals Leuven, Leuven, Belgium.
17
Centre de Génétique, Hôpital d'Enfants, CHU de Dijon et Université de Bourgogne, Dijon, France.
18
Child Neurology and Psychiatry Unit. Civil Hospital. Department of Clinical and Experimental Sciences, University of Brescia, Italy.
19
Service de Génétique Médicale, Inserm, CHU Nantes, UMR-S 957, Nantes, France.
20
Division of General Pediatrics, Department of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton, Canada.
21
Université et Faculté de Medecine Paris Descartes, Paris, France.
22
Department of Pediatrics, Clinical Genetics Program, McMaster Children's Hospital, McMaster University, Hamilton, Canada.
23
Department of Paediatric Neurology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
24
Clinics Hospital of Ribeirao Preto, University of São Paulo, Brasil.
25
O.U. Child Neuropsychiatry, Department of Neuroscience, Giannina Gaslini Institute, Genoa, Italy.
26
Institute of Infection Immunity and Inflammation, University of Glasgow, Glasgow, UK.
27
Institute for Neuroscience and Muscle Research, the Children's Hospital at Westmead, University of Sydney, Australia.
28
AP-HP, Department of Genetics, Groupe Hospitalier Pitié Salpêtrière, F-75013, Paris, France.
29
Paediatric Rheumatology, Giannina Gaslini Institute, Genoa, Italy.
30
Clinical Department of Pediatrics, San Paolo Hospital, University of Milan, Italy.
31
Department of Neurology, Great Ormond Street Hospital for Children, London, UK.
32
AP-HP, Service de Neuropédiatrie & Centre de Référence de Neurogénétique, Hôpital A. Trousseau, HUEP, F-75012 Paris, France.
33
UPMC Univ Paris 06, F-75012 Paris; Inserm U676, F-75019 Paris, France.
34
University of Cape Town, Red Cross War Memorial Children's Hospital, Republic of South Africa.
35
Department of Clinical Genetics, Southern General Hospital, Glasgow, Scotland, UK.
36
Department of Paediatric Neurology, Children's National Medical Center, Washington DC, USA.
37
Service de Néonatalogie et Réanimation, Hôpital Charles Nicolle, CHU Rouen, F-76031 Rouen, France.
38
Neurology Department. Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central, Portugal.
39
Division of Pediatric Neurology, Department of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton, Canada.
40
NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD, USA.
41
Paediatric Neurosciences Research Group, Fraser of Allander Neurosciences Unit, Royal Hospital for Sick Children, Glasgow, UK.
42
School of Medicine, College of Medical, Veterinary & Life Sciences, University of Glasgow, UK.
#
Contributed equally

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
PMCID:
PMC4004585
DOI:
10.1038/ng.2933
[Indexed for MEDLINE]
Free PMC Article

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