title: Characterization of samhd1 morphant zebrafish recapitulates features of the human type I interferonopathy Aicardi-Goutières syndrome.
abstract: In humans, loss of function mutations in the SAMHD1 (AGS5) gene cause a severe form of Aicardi-Goutières syndrome (AGS), an inherited inflammatory-mediated encephalopathy characterized by increased type I IFN activity and upregulation of IFN-stimulated genes (ISGs). In particular, SAMHD1-related AGS is associated with a distinctive cerebrovascular pathology that commonly leads to stroke. Although inflammatory responses are observed in immune cells cultured from Samhd1 null mouse models, these mice are physically healthy, specifically lacking a brain phenotype. We have investigated the use of zebrafish as an alternative system for generating a clinically relevant model of SAMHD1-related AGS. Using temporal gene knockdown of zebrafish samhd1, we observe hindbrain ventricular swelling and brain hemorrhage. Furthermore, loss of samhd1 or of another AGS-associated gene, adar, leads to a significant upregulation of innate immune-related genes and an increase in the number of cells expressing the zebrafish type I IFN ifnphi1. To our knowledge, this is the first example of an in vivo model of AGS that recapitulates features of both the innate immune and neurological characteristics of the disease. The phenotypes associated with loss of samhd1 and adar suggest a function of these genes in controlling innate immune processes conserved to zebrafish, thereby also contributing to our understanding of antiviral signaling in this model organism.
authors: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9WL, United Kingdom; paul.kasher@manchester.ac.uk.
authors: Paul R
authors: PR
authors: Kasher
authors: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9WL, United Kingdom;
authors: Emma M
authors: EM
authors: Jenkinson
authors: Institut Pasteur, Macrophages et Développement de l'Immunité, F-75015 Paris, France; Centre National de la Recherche Scientifique, Unité de Recherche Associée 2578, F-75015 Paris, France;
authors: Valérie
authors: V
authors: Briolat
authors: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9WL, United Kingdom;
authors: David
authors: D
authors: Gent
authors: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9WL, United Kingdom;
authors: Catherine
authors: C
authors: Morrissey
authors: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom; and.
authors: Leo A H
authors: LA
authors: Zeef
authors: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9WL, United Kingdom;
authors: Gillian I
authors: GI
authors: Rice
authors: Institut Pasteur, Macrophages et Développement de l'Immunité, F-75015 Paris, France; Centre National de la Recherche Scientifique, Unité de Recherche Associée 2578, F-75015 Paris, France;
authors: Jean-Pierre
authors: JP
authors: Levraud
authors: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9WL, United Kingdom; Laboratory of Neurogenetics and Neuroinflammation, Imagine Institute, Necker Hospital for Sick Children, 75015 Paris, France.
authors: Yanick J
authors: YJ
authors: Crow
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000235:genetics* / Q000378:metabolism; D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D020274:Autoimmune Diseases of the Nervous System / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002552:Cerebral Ventricles / Q000002:abnormalities / Q000378:metabolism; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007370:Interferon Type I / Q000235:genetics* / Q000378:metabolism; D007372:Interferons / Q000235:genetics / Q000378:metabolism; D020300:Intracranial Hemorrhages / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009421:Nervous System Malformations / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012249:Rhombencephalon / Q000002:abnormalities / Q000378:metabolism; D000076106:SAM Domain and HD Domain-Containing Protein 1; D017386:Sequence Homology, Amino Acid; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
chemical_list: D007370:Interferon Type I; D029961:Zebrafish Proteins; C543713:interferon phi1, zebrafish; D007372:Interferons; D000076106:SAM Domain and HD Domain-Containing Protein 1; C000598697:SAMHD1 protein, zebrafish; D000243:Adenosine Deaminase; D017766:Acid Anhydride Hydrolases