A common form of dominant human IFNAR1 deficiency impairs IFN-α and -ω but not IFN-β-dependent immunity
Authors: Al Qureshah Fahd , Le Pen Jérémie , de Weerd Nicole A. , Moncada-Velez Marcela , Materna Marie , Lin Daniel C. , Milisavljevic Baptiste , Vianna Fernanda , Bizien Lucy , Lorenzo Lazaro , Lecuit Marc , Pommier Jean-David , Keles Sevgi , Ozcelik Tayfun , Pedraza-Sanchez Sigifredo , de Prost Nicolas , El Zein Loubna , Hammoud Hassan , Ng Lisa F.P. , Halwani Rabih , Saheb Sharif-Askari Narjes , Lau Yu Lung , Tam Anthony R. , Singh Neha , Bhattad Sagar , Berkun Yackov , Chantratita Wasun , Aguilar-López Raúl , Shahrooei Mohammad ,   COVID-19 HGE Consortium, Abel Laurent , Aiuti Alessandro , Al-Muhsen Saleh , Alcántara-Garduño Ana Bertha , Andreakos Evangelos , Arias Andrés A. , Feldman Hagit Baris , Bastard Paul , Bolze Alexandre , Borghesi Alessandro , Bousfiha Ahmed A. , Brodin Petter , Christodoulou John , Cobat Aurélie , Colobran Roger , Condino-Neto Antonio , Duvlis Sotiriјa , Duval Xavier , Dündar Munis , Fakhreddine Soha , Fellay Jacques , Flores Carlos , Franco José Luis , Gorochov Guy , Gregersen Peter K. , Hagin David , Halwani Rabih , Herrera María Teresa , Hung Ivan Fan-Ngai , Jouanguy Emmanuelle , Lau Yu-Lung , Leung Daniel , Le-voyer Tom , Mansouri Davood , Mercado-García Jesús , Meyts Isabelle , Mogensen Trine H. , Ng Lisa F.P. , Novelli Antonio , Novelli Giuseppe , Okada Satoshi , Ozcelik Firat , Ozcelik Tayfun , de Diego Rebeca Perez , Perez-Tur Jordi , Pesole Graziano , Puel Anne , Renia Laurent , Resnick Igor , Rodríguez-Gallego Carlos , Sbeity Manal , Sedighzadeh Sahar , Shahrooei Mohammad , Soler-Palacín Pere , Spaan András N. , Tangye Stuart G. , Tayoun Ahmad Abou , Temel Şehime Gülsün , Thorball Christian , Torktaz Ibrahim , Trouillet-Assant Sophie , Turvey Stuart E. , Uddin Furkan , Vianna Fernanda Sales Luiz , Vinh Donald C. , Zabaleta-Martínez Oscar , Zhang Qian , Zhang Shen-Ying , Casanova Jean-Laurent ,   SEAe Consortium, Eng Chanreaksmey , Bun Kimrong , Oum MengHeng , Piola Patrice , Tarantola Arnaud , Channa Mey , Duong Veasna , Buchy Philippe , Gorman Chris , Pommier Jean-David , Crabol Yoann , Dussart Philippe , Bunleat M. , Panha M. , Sim M.Kanarith , Bunnakea Em , Laurent Denis , Sothy Heng , Santy Ky , Douangnouvong Anousone , Chommanam Danoy , Phakhounthong Khansoudaphone , Vongsouvath Manivanh , Seephone Malee , Sibounheunang Bountoy , Rattanavong Sayaphet , Davong Viengmon , Vongsouvath Malavanh , Mayxay Mayfong , Dubot-Pérès Audrey , Newton Paul N. , Phangmanixay Sommanikhone , Phongsavath Khounthavy , Anh Dang Duc , Quyen Do , Hung Tran Thi Mai , Thuy Nguyen Thi Thu , Tan Luong Minh , Pham Anh Tuan , Hien Nguyen , Huong Do Thu , Hai Le Thanh , Lam Nguyen Van , An Pham Nhat , Phuc Phan Huu , Thuy Phung Bich , Huong Tran Thi Thu , Hlaing Chaw Su , Aye Aye Mya Min , Thair Cho , Linn Kyaw , July May , Thein Win , Kyaw Latt Latt , Tin Htay Htay , Tin Ommar Swe , Oo Khin Yi , Crabol Yoann , Herrant Magali , Lago Magali , Seguy Maud , Jouan Marc , Hafner Lukas , Pérot Philippe , Eloit Marc , Lecuit Marc , Lortholary Olivier , Capelle Julien , Rosset Bruno , Chevalier Veronique , Honnorat Jérôme , Pinto Anne Laurie , Dubot-Peres Auey , de Lamballerie Xavier , Bleakley Kevin , Murgue Bernadette , Ferrant Catherine , Devaux Christian , Tissot-Dupont Hervé , Moatti Jean-Paul , Mayxay Mayfong , Bonnet Pascal , Fontenille Didier , Delfraissy Jean-François , Debré Patrice , Durand Benoit , Abel Laurent , Bastard Paul , Jouanguy Emmanuelle , Béziat Vivien , Zhang Peng , Rice Charles M. , Cobat Aurélie , Zhang Shen-Ying , Hertzog Paul J. , Casanova Jean-Laurent , Zhang Qian 
Published: December 2024

Autosomal recessive deficiency of the IFNAR1 or IFNAR2 chain of the human type I IFN receptor abolishes cellular responses to IFN-α, -β, and -ω, underlies severe viral diseases, and is globally very rare, except for IFNAR1 and IFNAR2 deficiency in Western Polynesia and the Arctic, respectively. We report 11 human IFNAR1 alleles, the products of which impair but do not abolish responses to IFN-α and -ω without affecting responses to IFN-β. Ten of these alleles are rare in all populations studied, but the remaining allele (P335del) is common in Southern China (minor allele frequency ≈2%). Cells heterozygous for these variants display a dominant phenotype in vitro with impaired responses to IFN-α and -ω, but not -β, and viral susceptibility. Negative dominance, rather than haploinsufficiency, accounts for this dominance. Patients heterozygous for these variants are prone to viral diseases, attesting to both the dominance of these variants clinically and the importance of IFN-α and -ω for protective immunity against some viruses.