Life-threatening viral disease in a novel form of autosomal recessive IFNAR2 deficiency in the Arctic

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  • Christopher J A Duncan, Clinical and Translational Research Institute, Immunity and Inflammation Theme, Newcastle University, Newcastle upon Tyne, UK, Storbritannien
  • Morten K Skouboe
  • Sophie Howarth, Clinical and Translational Research Institute, Immunity and Inflammation Theme, Newcastle University, Newcastle upon Tyne, UK, Storbritannien
  • Anne K Hollensen
  • Rui Chen, Clinical and Translational Research Institute, Immunity and Inflammation Theme, Newcastle University, Newcastle upon Tyne, UK, Storbritannien
  • Malene L Børresen, Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark., Danmark
  • Benjamin J Thompson, Clinical and Translational Research Institute, Immunity and Inflammation Theme, Newcastle University, Newcastle upon Tyne, UK, Storbritannien
  • Jarmila Stremenova Spegarova, Clinical and Translational Research Institute, Immunity and Inflammation Theme, Newcastle University, Newcastle upon Tyne, UK, Storbritannien
  • Catherine F Hatton, Clinical and Translational Research Institute, Immunity and Inflammation Theme, Newcastle University, Newcastle upon Tyne, UK, Storbritannien
  • Frederik F Stæger, Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark, Danmark
  • Mette K Andersen, The Novo Nordisk Foundation Center for Basic Metabolic Research, Københavns Universitet - Graduate School of Health and Medical Sciences Faculty of Health and Medical Sciences
  • ,
  • John Whittaker, Clinical and Translational Research Institute, Immunity and Inflammation Theme, Newcastle University, Newcastle upon Tyne, UK, Storbritannien
  • Søren R Paludan
  • Sofie E Jørgensen
  • Martin K Thomsen
  • Jacob G Mikkelsen
  • Carsten Heilmann, Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark., Danmark
  • Daniela Buhas, Department of Human Genetics, McGill University, Montreal, Quebec, Canada, Canada
  • Nina F Øbro, Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Danmark
  • Jakob T Bay, Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Danmark
  • Hanne V Marquart, Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Danmark
  • M Teresa de la Morena, Seattle Children's Hospital
  • ,
  • Joseph A Klejka, Yukon-Kuskokwim Health Corporation
  • ,
  • Matthew Hirschfeld, Alaska Native Medical Center
  • ,
  • Line Borgwardt, Center for Genomic Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark, Danmark
  • Isabel Forss, Center for Genomic Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark, Danmark
  • Tania Masmas, Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark., Danmark
  • Anja Poulsen, Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark., Danmark
  • Francisco Noya, Division of Allergy & Clinical Immunology, Montreal Children’s Hospital, Montreal General Hospital, McGill University, Montreal, Quebec, Canada, Canada
  • Guy Rouleau, The Neuro, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada, Canada
  • Torben Hansen, The Novo Nordisk Foundation Center for Basic Metabolic Research, Københavns Universitet - Graduate School of Health and Medical Sciences Faculty of Health and Medical Sciences
  • ,
  • Sirui Zhou, Department of Human Genetics, McGill University, Montréal, Québec, Canada., Canada
  • Anders Albrechtsen, Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark, Danmark
  • Reza Alizadehfar, Division of Allergy & Clinical Immunology, Montreal Children’s Hospital, Montreal General Hospital, McGill University, Montreal, Quebec, Canada, Canada
  • Eric J Allenspach, Seattle Children's Hospital, USA
  • Sophie Hambleton, Clinical and Translational Research Institute, Immunity and Inflammation Theme, Newcastle University, Newcastle upon Tyne, UK, Storbritannien
  • Trine H Mogensen

Type I interferons (IFN-I) play a critical role in human antiviral immunity, as demonstrated by the exceptionally rare deleterious variants of IFNAR1 or IFNAR2. We investigated five children from Greenland, Canada, and Alaska presenting with viral diseases, including life-threatening COVID-19 or influenza, in addition to meningoencephalitis and/or hemophagocytic lymphohistiocytosis following live-attenuated viral vaccination. The affected individuals bore the same homozygous IFNAR2 c.157T>C, p.Ser53Pro missense variant. Although absent from reference databases, p.Ser53Pro occurred with a minor allele frequency of 0.034 in their Inuit ancestry. The serine to proline substitution prevented cell surface expression of IFNAR2 protein, small amounts of which persisted intracellularly in an aberrantly glycosylated state. Cells exclusively expressing the p.Ser53Pro variant lacked responses to recombinant IFN-I and displayed heightened vulnerability to multiple viruses in vitro-a phenotype rescued by wild-type IFNAR2 complementation. This novel form of autosomal recessive IFNAR2 deficiency reinforces the essential role of IFN-I in viral immunity. Further studies are warranted to assess the need for population screening.

OriginalsprogEngelsk
Artikelnummere20212427
TidsskriftThe Journal of Experimental Medicine
Vol/bind219
Nummer6
Antal sider22
ISSN0022-1007
DOI
StatusUdgivet - jun. 2022

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