2. Academic Validation
  3. Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children

Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children

  • Science. 2023 Feb 10;379(6632):eabo3627. doi: 10.1126/science.abo3627.
Danyel Lee 1 2 3,  Jérémie Le Pen # 4,  Ahmad Yatim # 1,  Beihua Dong # 5,  Yann Aquino # 6 7,  Masato Ogishi # 1,  Rémi Pescarmona # 8,  Estelle Talouarn # 2 3,  Darawan Rinchai # 1,  Peng Zhang # 1,  Magali Perret # 8,  Zhiyong Liu 1,  Iolanda Jordan 9 10 11 12 13,  Sefika Elmas Bozdemir 14,  Gulsum Iclal Bayhan 15,  Camille Beaufils 16,  Lucy Bizien 2 3,  Aurelie Bisiaux 6,  Weite Lei 1,  Milena Hasan 17,  Jie Chen 1,  Christina Gaughan 5,  Abhishek Asthana 5,  Valentina Libri 17,  Joseph M Luna 4 18,  Fabrice Jaffré 19,  H-Heinrich Hoffmann 4,  Eleftherios Michailidis 4 20,  Marion Moreews 21,  Yoann Seeleuthner 2 3,  Kaya Bilguvar 22 23,  Shrikant Mane 24,  Carlos Flores 25 26 27,  Yu Zhang 28 29,  Andrés A Arias 1 30 31,  Rasheed Bailey 1,  Agatha Schlüter 32,  Baptiste Milisavljevic 1,  Benedetta Bigio 1,  Tom Le Voyer 2 3,  Marie Materna 2 3,  Adrian Gervais 2 3,  Marcela Moncada-Velez 1,  Francesca Pala 28,  Tomi Lazarov 33,  Romain Levy 2 3,  Anna-Lena Neehus 2 3,  Jérémie Rosain 2 3,  Jessica Peel 1,  Yi-Hao Chan 1,  Marie-Paule Morin 16,  Rosa Maria Pino-Ramirez 34,  Serkan Belkaya 35,  Lazaro Lorenzo 1,  Jordi Anton 12 36 37,  Selket Delafontaine 38,  Julie Toubiana 39 40,  Fanny Bajolle 41,  Victoria Fumadó 10 12 42 43,  Marta L DeDiego 44,  Nadhira Fidouh 45,  Flore Rozenberg 46,  Jordi Pérez-Tur 47 48 49,  Shuibing Chen 19,  Todd Evans 19,  Frédéric Geissmann 33,  Pierre Lebon 50,  Susan R Weiss 51,  Damien Bonnet 41,  Xavier Duval 52 53 54 55,  CoV-Contact Cohort§,  COVID Human Genetic Effort¶,  Qiang Pan-Hammarström 56,  Anna M Planas 57 58,  Isabelle Meyts 59,  Filomeen Haerynck 60,  Aurora Pujol 61 62,  Vanessa Sancho-Shimizu 63 64,  Clifford L Dalgard 65 66,  Jacinta Bustamante 1 2 3 67,  Anne Puel 1 2 3,  Stéphanie Boisson-Dupuis 1 2 3,  Bertrand Boisson 1 2 3,  Tom Maniatis 68,  Qian Zhang 1 2 3,  Paul Bastard 1 2 3 69,  Luigi Notarangelo 28,  Vivien Béziat 1 2 3,  Rebeca Perez de Diego 70 71,  Carlos Rodriguez-Gallego 72 73,  Helen C Su 28 29,  Richard P Lifton 24 74,  Emmanuelle Jouanguy 1 2 3,  Aurélie Cobat # 1 2 3,  Laia Alsina # 10 12 37 75,  Sevgi Keles # 76,  Elie Haddad # 77,  Laurent Abel # 1 2 3,  Alexandre Belot # 21 78,  Lluis Quintana-Murci # 6 79,  Charles M Rice # 4,  Robert H Silverman # 5,  Shen-Ying Zhang # 1 2 3,  Jean-Laurent Casanova # 1 2 3 80 81
Affiliations

Affiliations

  • 1 St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
  • 2 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
  • 3 Paris City University, Imagine Institute, Paris, France.
  • 4 Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
  • 5 Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
  • 6 Human Evolutionary Genetics Unit, Institut Pasteur, Paris City University, CNRS UMR 2000, Paris, France.
  • 7 Doctoral College, Sorbonne University, Paris, France.
  • 8 Laboratory of Immunology, Lyon Sud Hospital, Lyon, France.
  • 9 Pediatric Intensive Care Department, Hospital Sant Joan de Déu, Barcelona, Spain.
  • 10 Kids Corona Platform, Barcelona, Spain.
  • 11 Center for Biomedical Network Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain.
  • 12 Department of Surgery and Surgical Specializations, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.
  • 13 Respiratory and Immunological Dysfunction in Pediatric Critically Ill Patients, Institute of Recerca Sant Joan de Déu, Barcelona, Spain.
  • 14 Bursa City Hospital, Bursa, Turkey.
  • 15 Ankara City Hospital, Yildirim Beyazit University, Ankara, Turkey.
  • 16 Immunology and Rheumatology Division, Department of Pediatrics, University of Montreal, CHU Sainte-Justine, Montreal, QC, Canada.
  • 17 Center for Translational Research, Institut Pasteur, Paris City University, Paris, France.
  • 18 Department of Biochemistry and Center for RNA Science and Therapeutics, Case Western Reserve University, Cleveland, OH, USA.
  • 19 Department of Surgery, Weill Cornell Medical College, New York, NY, USA.
  • 20 Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA, USA.
  • 21 International Center of Infectiology Research (CIRI), University of Lyon, INSERM U1111, Claude Bernard University, Lyon 1, CNRS, UMR5308, ENS of Lyon, Lyon, France.
  • 22 Departments of Neurosurgery and Genetics and Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT, USA.
  • 23 Department of Medical Genetics, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey.
  • 24 Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
  • 25 Research Unit, Nuestra Señora de la Candelaria University Hospital, Santa Cruz de Tenerife, Spain.
  • 26 Genomics Division, Institute of Technology and Renewable Energies (ITER), Granadilla de Abona, Spain.
  • 27 CIBERES, ISCIII, Madrid, Spain.
  • 28 Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAID, NIH, Bethesda, MD, USA.
  • 29 NIAID Clinical Genomics Program, NIH, Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAID, NIH, Bethesda, MD, USA.
  • 30 Primary Immunodeficiencies Group, University of Antioquia (UdeA), Medellin, Colombia.
  • 31 School of Microbiology, University of Antioquia (UdeA), Medellin, Colombia.
  • 32 Neurometabolic Diseases Laboratory, IDIBELL-Hospital Duran I Reynals, CIBERER U759, ISIiii, Madrid, Spain.
  • 33 Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 34 Pediatrics Department, Hospital Sant Joan de Déu, Barcelona, Spain.
  • 35 Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey.
  • 36 Pediatric Rheumatology Division, Hospital Sant Joan de Déu, Barcelona, Spain.
  • 37 Study Group for Immune Dysfunction Diseases in Children (GEMDIP), Institute of Recerca Sant Joan de Déu, Barcelona, Spain.
  • 38 Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium.
  • 39 Department of General Pediatrics and Pediatric Infectious Diseases, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris City University, Paris, France.
  • 40 Biodiversity and Epidemiology of Bacterial Pathogens, Pasteur Institute, Paris, France.
  • 41 Department of Pediatric Cardiology, Necker Hospital for Sick Children, AP-HP, Paris City University, Paris, France.
  • 42 Pediatrics Infectious Diseases Division, Hospital Sant Joan de Déu, Barcelona, Spain.
  • 43 Infectious Diseases and Microbiome, Institute of Recerca Sant Joan de Déu, Barcelona, Spain.
  • 44 Department of Molecular and Cellular Biology, National Center for Biotechnology (CNB-CSIC), Madrid, Spain.
  • 45 Laboratory of Virology, Bichat-Claude Bernard Hospital, Paris, France.
  • 46 Laboratory of Virology, AP-HP, Cochin Hospital, Paris, France.
  • 47 Molecular Genetics Unit, Institute of Biomedicine of Valencia (IBV-CSIC), Valencia, Spain.
  • 48 CIBERNED, ISCIII, Madrid, Spain.
  • 49 Joint Research Unit in Neurology and Molecular Genetics, Institut of Investigation Sanitaria La Fe, Valencia, Spain.
  • 50 Medical School, Paris City University, Paris, France.
  • 51 Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 52 Bichat-Claude Bernard Hospital, Paris, France.
  • 53 University Paris Diderot, Paris 7, UFR of Médecine-Bichat, Paris, France.
  • 54 IAME, INSERM, UMRS1137, Paris City University, Paris, France.
  • 55 Infectious and Tropical Diseases Department, AP-HP, Bichat-Claude Bernard Hospital, Paris, France.
  • 56 Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
  • 57 Department of Neuroscience and Experimental Therapeutics, Institute for Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona, Spain.
  • 58 Institute for Biomedical Investigations August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
  • 59 Department of Pediatrics, University Hospitals Leuven and Laboratory for Inborn Errors of Immunity, KU Leuven, Leuven, Belgium.
  • 60 Primary Immunodeficiency Research Laboratory, Center for Primary Immunodeficiency Ghent, Ghent University Hospital, Ghent, Belgium.
  • 61 Neurometabolic Diseases Laboratory, IDIBELL-Hospital Duran I Reynals; and Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.
  • 62 CIBERER U759, ISCiii, Madrid, Spain.
  • 63 Department of Paediatric Infectious Diseases and Virology, Imperial College London, London, UK.
  • 64 Centre for Paediatrics and Child Health, Faculty of Medicine, Imperial College London, London, UK.
  • 65 The American Genome Center, Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
  • 66 Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
  • 67 Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, AP-HP, Paris, France.
  • 68 New York Genome Center, New York, NY, USA.
  • 69 Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France.
  • 70 Laboratory of Immunogenetics of Human Diseases, Innate Immunity Group, IdiPAZ Institute for Health Research, La Paz Hospital, Madrid, Spain.
  • 71 Interdepartmental Group of Immunodeficiencies, Madrid, Spain.
  • 72 Department of Clinical Sciences, University Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain.
  • 73 Department of Immunology, University Hospital of Gran Canaria Dr. Negrín, Canarian Health System, Las Palmas de Gran Canaria, Spain.
  • 74 Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.
  • 75 Clinical Immunology and Primary Immunodeficiencies Unit, Pediatric Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu, Barcelona, Spain.
  • 76 Necmettin Erbakan University, Konya, Turkey.
  • 77 Department of Pediatrics, Department of Microbiology, Immunology and Infectious Diseases, University of Montreal and Immunology and Rheumatology Division, CHU Sainte-Justine, Montreal, QC, Canada.
  • 78 National Reference Center for Rheumatic, Autoimmune and Systemic Diseases in Children (RAISE), Pediatric Nephrology, Rheumatology, Dermatology Unit, Hospital of Mother and Child, Hospices Civils of Lyon, Lyon, France.
  • 79 Human Genomics and Evolution, Collège de France, Paris, France.
  • 80 Department of Pediatrics, Necker Hospital for Sick Children, Paris, France.
  • 81 Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA.
  • # Contributed equally.
PMID: 36538032 DOI: 10.1126/science.abo3627
Abstract

Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.

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