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

2022; Rockefeller University Press; Volume: 219; Issue: 6 Linguagem: Inglês

10.1084/jem.20220028

1540-9538

Paul Bastard, Kuang‐Chih Hsiao, Qian Zhang, Jérémy Choin, Emma Best, Jie Chen, Adrian Gervais, Lucy Bizien, Marie Materna, Christine Harmant, Maguelonne Roux, Nicola L. Hawley, Daniel E. Weeks, Stephen T. McGarvey, Karla Sandoval, Carmina Barberena-Jonas, Consuelo D. Quinto-Cortés, Erika Hagelberg, Alexander J. Mentzer, Kathryn Robson, Boubacar Coulibaly, Yoann Seeleuthner, Benedetta Bigio, Zhi Li, Gilles Uzé, Sandra Pellegrini, Lazaro Lorenzo, Zineb Sbihi, Sylvain Latour, Marianne Besnard, Tiphaine Adam de Beaumais, Evelyne Jacqz‐Aigrain, Vivien Béziat, Ranjan Deka, Litara Esera Tulifau, Satupaitea Viali, Muagututi‘a Sefuiva Reupena, Take Naseri, Peter McNaughton, Vanessa Sarkozy, Jane Peake, Annaliesse Blincoe, Sarah Primhak, Simon Stables, Kate Gibson, See‐Tarn Woon, Kylie M. Drake, Adrian V. S. Hill, Cheng-Yee Chan, Richard King, Rohan Ameratunga, Iotefa Teiti, Maïté Aubry, Van‐Mai Cao‐Lormeau, Stuart G. Tangye, Shen‐Ying Zhang, Emmanuelle Jouanguy, Paul Gray, Laurent Abel, Andrés Moreno‐Estrada, Ryan L. Minster, Lluís Quintana‐Murci, Andrew Wood, Jean‐Laurent Casanova,

Blood disorders and treatments

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.