title: Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling.
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.
authors.affiliation: Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, UK.
authors.forename: Gillian I
authors.initials: GI
authors.lastname: Rice
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.|Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Yoandris
authors.initials: Y
authors.lastname: Del Toro Duany
authors.affiliation: Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, UK.
authors.forename: Emma M
authors.initials: EM
authors.lastname: Jenkinson
authors.affiliation: Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, UK.
authors.forename: Gabriella Ma
authors.initials: GM
authors.lastname: Forte
authors.affiliation: Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, UK.
authors.forename: Beverley H
authors.initials: BH
authors.lastname: Anderson
authors.affiliation: Child Neurology and Psychiatry Unit, C. Mondino National Neurological Institute, Pavia, Italy.|Department of Brain and Behavioral Sciences, Unit of Child Neurology and Psychiatry, University of Pavia, Pavia, Italy.
authors.forename: Giada
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authors.lastname: Ariaudo
authors.affiliation: Department of pediatric Immunology and Rheumatology, INSERM U 768, Imagine Foundation, APHP, Hôpital Necker, Paris, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bader-Meunier
authors.affiliation: Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Baildam
authors.affiliation: Department of Developmental Neuroscience, IRCCS Stella Maris, Pisa, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Battini
authors.affiliation: Institute of Translational Medicine, University of Liverpool; Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Beresford
authors.affiliation: Department of Developmental Neuroscience, IRCCS Stella Maris, Pisa, Italy.
authors.forename: Manuela
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authors.affiliation: Service de Pédiatrie 1, CHU de Dijon, Dijon, France.
authors.forename: Mondher
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authors.forename: Abigail E
authors.initials: AE
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authors.affiliation: Department of Paediatrics, Rainbow House NHS Ayrshire & Arran, Scotland, UK.
authors.forename: Nuno Jv
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authors.affiliation: Neuroimmunology group, the Children's Hospital at Westmead, University of Sydney, Australia.
authors.forename: Russell C
authors.initials: RC
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authors.affiliation: Department of Paediatric Rheumatology, Royal Hospital for Sick Children, Glasgow, UK.
authors.forename: Joyce E
authors.initials: JE
authors.lastname: Davidson
authors.affiliation: Department of Development and Regeneration, KU Leuven, Paediatric Neurology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: De Waele
authors.affiliation: Department of pediatric Immunology and Rheumatology, INSERM U 768, Imagine Foundation, APHP, Hôpital Necker, Paris, France.
authors.forename: Isabelle
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authors.lastname: Desguerre
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authors.forename: Laurence
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authors.forename: Elisa
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authors.affiliation: Service de Génétique Médicale, Inserm, CHU Nantes, UMR-S 957, Nantes, France.
authors.forename: Bertrand
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authors.affiliation: Department of Development and Regeneration, KU Leuven, Paediatric Neurology, University Hospitals Leuven, Leuven, Belgium.
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authors.affiliation: Division of General Pediatrics, Department of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton, Canada.
authors.forename: Andrew R
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authors.affiliation: Université et Faculté de Medecine Paris Descartes, Paris, France.
authors.forename: Pierre
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authors.affiliation: Department of Pediatrics, Clinical Genetics Program, McMaster Children's Hospital, McMaster University, Hamilton, Canada.
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authors.affiliation: Department of Paediatric Neurology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
authors.forename: John H
authors.initials: JH
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authors.affiliation: Clinics Hospital of Ribeirao Preto, University of São Paulo, Brasil.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Lourenço
authors.affiliation: O.U. Child Neuropsychiatry, Department of Neuroscience, Giannina Gaslini Institute, Genoa, Italy.
authors.forename: Maria Margherita
authors.initials: MM
authors.lastname: Mancardi
authors.affiliation: Centre de Génétique, Hôpital d'Enfants, CHU de Dijon et Université de Bourgogne, Dijon, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Masurel-Paulet
authors.affiliation: Institute of Infection Immunity and Inflammation, University of Glasgow, Glasgow, UK.
authors.forename: Iain B
authors.initials: IB
authors.lastname: McInnes
authors.affiliation: Institute for Neuroscience and Muscle Research, the Children's Hospital at Westmead, University of Sydney, Australia.
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authors.forename: Cyril
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authors.affiliation: Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, UK.
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authors.lastname: O'Sullivan
authors.affiliation: Child Neurology and Psychiatry Unit, C. Mondino National Neurological Institute, Pavia, Italy.
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authors.affiliation: Department of Neurology, Great Ormond Street Hospital for Children, London, UK.
authors.forename: Robert A
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authors.affiliation: AP-HP, Service de Neuropédiatrie & Centre de Référence de Neurogénétique, Hôpital A. Trousseau, HUEP, F-75012 Paris, France.|UPMC Univ Paris 06, F-75012 Paris; Inserm U676, F-75019 Paris, France.
authors.forename: Diana
authors.initials: D
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authors.affiliation: Clinical Department of Pediatrics, San Paolo Hospital, University of Milan, Italy.
authors.forename: Elisabetta
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authors.affiliation: University of Cape Town, Red Cross War Memorial Children's Hospital, Republic of South Africa.
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authors.affiliation: Department of Pediatrics, Clinical Genetics Program, McMaster Children's Hospital, McMaster University, Hamilton, Canada.
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authors.lastname: Szybowska
authors.affiliation: Department of Clinical Genetics, Southern General Hospital, Glasgow, Scotland, UK.
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authors.initials: JL
authors.lastname: Tolmie
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authors.initials: C
authors.lastname: Vanhulle
authors.affiliation: Neurology Department. Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central, Portugal.
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authors.initials: JP
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authors.affiliation: University of Cape Town, Red Cross War Memorial Children's Hospital, Republic of South Africa.
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authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton, Canada.
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authors.initials: RN
authors.lastname: Whitney
authors.affiliation: Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, UK.
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authors.initials: SG
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authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD, USA.
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authors.affiliation: Paediatric Neurosciences Research Group, Fraser of Allander Neurosciences Unit, Royal Hospital for Sick Children, Glasgow, UK.|School of Medicine, College of Medical, Veterinary & Life Sciences, University of Glasgow, UK.
authors.forename: Sameer M
authors.initials: SM
authors.lastname: Zuberi
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.|Boston Children's Hospital, Boston, MA 02115, USA.
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authors.affiliation: Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, UK.
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mesh_terms: D000704:Analysis of Variance; D020274:Autoimmune Diseases of the Nervous System / Q000235:genetics* / Q000276:immunology; D001483:Base Sequence; D053487:DEAD-box RNA Helicases / Q000737:chemistry / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D059472:Exome / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007370:Interferon Type I / Q000276:immunology*; D000072640:Interferon-Induced Helicase, IFIH1; D018895:Microsatellite Repeats / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009421:Nervous System Malformations / Q000235:genetics* / Q000276:immunology; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics*; D013057:Spectrum Analysis
chemical_list: D007370:Interferon Type I; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1