A loss-of-function IFNAR1 allele in Polynesia underlies severe viral diseases in homozygotes.

Publisher: Rockefeller University Press Country of Publication: United States NLM ID: 2985109R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1540-9538 (Electronic) Linking ISSN: 00221007 NLM ISO Abbreviation: J Exp Med Subsets: MEDLINE

Original Publication: New York, NY : Rockefeller University Press

Receptor, Interferon alpha-beta* ; Virus Diseases*; Alleles ; Child ; Homozygote ; Humans ; Polynesia

Globally, autosomal recessive IFNAR1 deficiency is a rare inborn error of immunity underlying susceptibility to live attenuated vaccine and wild-type viruses. We report seven children from five unrelated kindreds of western Polynesian ancestry who suffered from severe viral diseases. All the patients are homozygous for the same nonsense IFNAR1 variant (p.Glu386*). This allele encodes a truncated protein that is absent from the cell surface and is loss-of-function. The fibroblasts of the patients do not respond to type I IFNs (IFN-α2, IFN-ω, or IFN-β). Remarkably, this IFNAR1 variant has a minor allele frequency >1% in Samoa and is also observed in the Cook, Society, Marquesas, and Austral islands, as well as Fiji, whereas it is extremely rare or absent in the other populations tested, including those of the Pacific region. Inherited IFNAR1 deficiency should be considered in individuals of Polynesian ancestry with severe viral illnesses.
(© 2022 Bastard et al.)

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R01AI088364 United States NH NIH HHS; U01 HL120393 United States HL NHLBI NIH HHS; UL1 TR001866 United States TR NCATS NIH HHS; HHSN268201100037C United States HL NHLBI NIH HHS; UM1 HG006504 United States HG NHGRI NIH HHS; R01 HL133040 United States HL NHLBI NIH HHS; R01 HL120393 United States HL NHLBI NIH HHS; UM1HG006504 United States HG NHGRI NIH HHS; UL1 TR001863 United States TR NCATS NIH HHS; S10 OD018521 United States OD NIH HHS; United States HHMI Howard Hughes Medical Institute; UL1 RR024143 United States RR NCRR NIH HHS; HHSN268201800001C United States HL NHLBI NIH HHS; HHSN268201500016C United States HL NHLBI NIH HHS; R01 AI088364 United States AI NIAID NIH HHS; R01 HL093093 United States HL NHLBI NIH HHS; MR/N028937/1 United Kingdom MRC_ Medical Research Council; R01 HL117626 United States HL NHLBI NIH HHS; R01 AI163029 United States AI NIAID NIH HHS; U24 HG008956 United States HG NHGRI NIH HHS

0 (IFNAR1 protein, human)
156986-95-7 (Receptor, Interferon alpha-beta)

Date Created: 20220420 Date Completed: 20220422 Latest Revision: 20230516

20240104

PMC9026234

10.1084/jem.20220028

35442418