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

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        1 , 2 , 3 , 1 , 1 , 1 , 4 , 5 , 6 , 7 , 8 , 9 , 8 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 6 , 17 , 18 , 19 , 16 , 20 , 21 , 22 , 23 , 24 , 25 , 17 ,   26 , 27 , 28 , 1 , 4 , 29 , 30 , 31 , 32 , 33 , 30 , 34 , 22 , 35 , 36 , 37 , 38 , 34 , 39 , 1 , 40 , 41 , 42 , 2 , 3 , * , 1 , *
      Nature genetics

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          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 patients with 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 ( MDA5) cause a spectrum of neuro-immunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer a gain-of-function - so 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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          Most cited references21

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          Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus.

          Systemic lupus erythematosus (SLE) is a complex, inflammatory autoimmune disease that affects multiple organ systems. We used global gene expression profiling of peripheral blood mononuclear cells to identify distinct patterns of gene expression that distinguish most SLE patients from healthy controls. Strikingly, about half of the patients studied showed dysregulated expression of genes in the IFN pathway. Furthermore, this IFN gene expression "signature" served as a marker for more severe disease involving the kidneys, hematopoetic cells, and/or the central nervous system. These results provide insights into the genetic pathways underlying SLE, and identify a subgroup of patients who may benefit from therapies targeting the IFN pathway.
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            Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus.

            Aicardi-Goutières syndrome (AGS) presents as a severe neurological brain disease and is a genetic mimic of the sequelae of transplacentally acquired viral infection. Evidence exists for a perturbation of innate immunity as a primary pathogenic event in the disease phenotype. Here, we show that TREX1, encoding the major mammalian 3' --> 5' DNA exonuclease, is the AGS1 gene, and AGS-causing mutations result in abrogation of TREX1 enzyme activity. Similar loss of function in the Trex1(-/-) mouse leads to an inflammatory phenotype. Our findings suggest an unanticipated role for TREX1 in processing or clearing anomalous DNA structures, failure of which results in the triggering of an abnormal innate immune response.
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              Structural basis for dsRNA recognition, filament formation, and antiviral signal activation by MDA5.

              MDA5, a viral double-stranded RNA (dsRNA) receptor, shares sequence similarity and signaling pathways with RIG-I yet plays essential functions in antiviral immunity through distinct specificity for viral RNA. Revealing the molecular basis for the functional divergence, we report here the crystal structure of MDA5 bound to dsRNA, which shows how, using the same domain architecture, MDA5 recognizes the internal duplex structure, whereas RIG-I recognizes the terminus of dsRNA. We further show that MDA5 uses direct protein-protein contacts to stack along dsRNA in a head-to-tail arrangement, and that the signaling domain (tandem CARD), which decorates the outside of the core MDA5 filament, also has an intrinsic propensity to oligomerize into an elongated structure that activates the signaling adaptor, MAVS. These data support a model in which MDA5 uses long dsRNA as a signaling platform to cooperatively assemble the core filament, which in turn promotes stochastic assembly of the tandem CARD oligomers for signaling. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                7 March 2014
                30 March 2014
                May 2014
                01 November 2014
                : 46
                : 5
                : 503-509
                Affiliations
                [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
                Author notes
                [§]

                These authors jointly directed this work.

                Author contributions

                Exome sequencing was performed by B.H.A., J.O’.S., and S.G.W. Exome data analysis was performed by E.J., G.I.R. and Y.J.C. G.I.R. performed qPCR analysis and Sanger sequencing with assistance from E.J. and G.M.A.F. G.M.A.F and B.H.A performed genotyping analysis with assistance from G.I.R. IFIH1 protein studies were performed by Y.d.T.D. Modeling studies were performed by S.H. Y.J.C. and S.H. designed and supervised the project and wrote the manuscript supported by G.I.R. G.A., B.B-M., E.M.B., R.B., M.W.B., M.C., M.C., 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., S.M.Z. identified affected patients, or assisted with related clinical and laboratory studies.

                Article
                EMS57307
                10.1038/ng.2933
                4004585
                24686847
                3cef8a88-919a-47a8-90d6-d4b0ae496aa7
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                Genetics
                Genetics

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