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

Jean-Laurent Casanova (1, 2, 3, 4, 5) , Andrew Wood (6) , Lluis Quintana-Murci (7, 8) , Ryan Minster (9) , Andrés Moreno-Estrada (10) , Laurent Abel (3, 1, 2, 4) , Paul Gray (11, 12) , Emmanuelle Jouanguy (1, 2, 3, 4) , Shen-Ying Zhang (1, 2, 3, 4) , Stuart Tangye (13, 14) , Van-Mai Cao-Lormeau (15) , Maite Aubry (15) , Iotefa Teiti (15) , Rohan Ameratunga (16, 6) , Richard King (17) , Cheng-Yee Chan (17) , Adrian Hill (18) , Kylie Drake (17) , See-Tarn Woon (16, 6) , Kate Gibson , Simon Stables (16) , Sarah Primhak (6) , Annaliesse Blincoe , Jane Peake (19) , Vanessa Sarkozy (11, 12) , Peter Mcnaughton (19) , Take Naseri (20, 21) , Muagututi‘a Reupena , Satupa‘itea Viali , Litara Esera Tulifau (22) , Ranjan Deka (23) , Vivien Béziat (1, 4) , Evelyne Jacqz Aigrain (24, 25) , Tiphaine Adam de Beaumais (26, 24) , Marianne Besnard (27) , Sylvain Latour (1) , Zineb Sbihi (1) , Lazaro Lorenzo (1, 4) , Sandra Pellegrini (28) , Gilles Uzé (29) , Zhi Li (28, 7) , Benedetta Bigio (2) , Yoann Seeleuthner (1, 4) , Boubacar Coulibaly (1, 4) , Kathryn Robson (18) , Alexander Mentzer (18) , Erika Hagelberg (30) , Consuelo Quinto-Cortés (31) , Carmina Barberena-Jonas (31) , Karla Sandoval (31) , Stephen Mcgarvey (20) , Daniel Weeks (9) , Nicola Hawley (32, 20) , Maguelonne Roux (7, 33) , Christine Harmant (7) , Marie Materna (1, 34, 4) , Lucy Bizien (1, 34, 4) , Adrian Gervais (1, 34, 4) , Jie Chen (2, 35) , Emma Best (6) , Jeremy Choin (7) , Qian Zhang (34, 2, 1, 4) , Kuang-Chih Hsiao (6, 36) , Paul Bastard (34, 2, 1, 4)

1 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
2 Rockefeller University [New York]
3 Equipe Inserm U1163 - Human genetics of infectious diseases: Complex predisposition
4 Département de Pédiatrie et maladies infectieuses [CHU Necker]
5 HHMI - Howard Hughes Medical Institute
6 University of Auckland [Auckland]
7 Génétique Evolutive Humaine - Human Evolutionary Genetics
8 Collège de France - Chaire Génomique humaine et évolution
9 PITT - University of Pittsburgh
10 CINVESTAV - Langebio
11 UNSW - University of New South Wales [Sydney]
12 Sydney Children's hospital
13 Garvan Institute of medical research
14 UNSW Faculty of Medicine [Sydney]
15 ILM - Institut Louis Malardé [Papeete]
16 Auckland City Hospital
17 Canterbury Health Laboratories
18 University of Oxford
19 University of Queensland [Brisbane]
20 Brown University
21 Ministry of Health [Samoa]
22 TTM - Tupua Tamasese Meaole Hospital
23 UC - University of Cincinnati
24 AP-HP - Hopital Saint-Louis [AP-HP]
25 UPCité - Université Paris Cité
26 IGR - Institut Gustave Roussy
27 Centre Hospitalier de Polynésie Française
28 Signalisation des Cytokines - Cytokine Signaling
29 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
30 UiO - University of Oslo
31 LANGEBIO - National Laboratory of Genomics for Biodiversity
32 Yale University [New Haven]
33 Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB
34 Equipe Inserm U1163 - Human genetics of infectious diseases : Mendelian predisposition
35 Shanghai Jiaotong University
36 MCRI - Murdoch Children's Research Institute

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.

Keywords: Human disease genetics; Immunodeficiency; Infectious disease and host defense; Innate immunity and inflammation

Domains: Life Sciences [q-bio]; Genetics; Life Sciences [q-bio]; Human health and pathology; Infectious diseases

Jean-Laurent Casanova, Andrew Wood, Lluis Quintana-Murci, Ryan Minster, Andrés Moreno-Estrada, et al.. A loss-of-function IFNAR1 allele in Polynesia underlies severe viral diseases in homozygotes. Journal of Experimental Medicine, 2022, 219 (6), pp.e20220028. ⟨10.1084/jem.20220028⟩. ⟨pasteur-03681917⟩