Life-threatening viral disease in a novel form of autosomal recessive IFNAR2 deficiency in the Arctic.
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
06 06 2022
06 06 2022
Historique:
received:
05
12
2021
revised:
28
02
2022
accepted:
21
03
2022
entrez:
20
4
2022
pubmed:
21
4
2022
medline:
23
4
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35442417
pii: 213169
doi: 10.1084/jem.20212427
pmc: PMC9026249
pii:
doi:
Substances chimiques
Antiviral Agents
0
IFNAR2 protein, human
0
Interferon Type I
0
Receptor, Interferon alpha-beta
156986-95-7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Wellcome Trust
ID : 207556/Z/17/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/NO13840/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 211153/Z/18/Z
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022 Duncan et al.
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