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

Lookup NU author(s): Dr Christopher DuncanORCiD, Sophie Howarth, Dr Rui ChenORCiD, Dr Benjamin Thompson, Dr Jarmila SpegarovaORCiD, Catherine Hatton, John Whittaker, Professor Sophie HambletonORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.

Publication metadata

Author(s): Duncan CJA, Skouboe MK, Howarth S, Hollensen AK, Chen R, Borresen ML, Thompson BJ, Spegarova JS, Hatton CF, Staeger FF, Andersen MK, Whittaker J, Paludan SR, Jorgensen SE, Thomsen MK, Mikkelsen JG, Heilmann C, Buhas D, Orbo NF, Bay JT, Marquart HV, De la Morena MT, Klejka JA, Hirschfeld M, Bogwardt L, Forss I, Masmas T, Poulsen A, Noya F, Rouleau G, Hansen T, Zhou S, Abrechtsen A, Alizadehfar R, Allenspach EJ, Hambleton S, Mogensen TH

Publication type: Article

Publication status: Published

Journal: Journal of Experimental Medicine

Year: 2022

Volume: 219

Issue: 6

Online publication date: 20/04/2022

Acceptance date: 21/03/2022

Date deposited: 22/06/2022

ISSN (print): 0022-1007

ISSN (electronic): 1540-9538

Publisher: Rockefeller University Press


DOI: 10.1084/jem.20212427

PubMed id: 35442417


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Funder referenceFunder name
207556/Z/17/ZWellcome Trust
211153/Z/18/ZWellcome Trust
The Independent Research Fund Denmark
the Lundbeck Foundation
the NOVO Nordisk Foundation