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

Bastard P., Hsiao K-C., Zhang Q., Choin J., Best E., Chen J., Gervais A., Bizien L., Materna M., Harmant C., Roux M., Hawley NL., Weeks DE., McGarvey ST., Sandoval K., Barberena-Jonas C., Quinto-Cortés CD., Hagelberg E., Mentzer AJ., Robson K., Coulibaly B., Seeleuthner Y., Bigio B., Li Z., Uzé G., Pellegrini S., Lorenzo L., Sbihi Z., Latour S., Besnard M., Adam de Beaumais T., Jacqz Aigrain E., Béziat V., Deka R., Esera Tulifau L., Viali S., Reupena MS., Naseri T., McNaughton P., Sarkozy V., Peake J., Blincoe A., Primhak S., Stables S., Gibson K., Woon S-T., Drake KM., Hill AVS., Chan C-Y., King R., Ameratunga R., Teiti I., Aubry M., Cao-Lormeau V-M., Tangye SG., Zhang S-Y., Jouanguy E., Gray P., Abel L., Moreno-Estrada A., Minster RL., Quintana-Murci L., Wood AC., Casanova J-L.

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.

DOI

10.1084/jem.20220028

Type

Journal article

Journal

The Journal of experimental medicine

Publication Date

06/2022

Volume

219

Addresses

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.

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