Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children
Authors: Lee Danyel , Le Pen Jérémie , Yatim Ahmad , Dong Beihua , Aquino Yann , Ogishi Masato , Pescarmona Rémi , Talouarn Estelle , Rinchai Darawan , Zhang Peng , Perret Magali , Liu Zhiyong , Jordan Iolanda , Elmas Bozdemir Sefika , Bayhan Gulsum Iclal , Beaufils Camille , Bizien Lucy , Bisiaux Aurelie , Lei Weite , Hasan Milena , Chen Jie , Gaughan Christina , Asthana Abhishek , Libri Valentina , Luna Joseph M. , Jaffré Fabrice , Hoffmann H.-Heinrich , Michailidis Eleftherios , Moreews Marion , Seeleuthner Yoann , Bilguvar Kaya , Mane Shrikant , Flores Carlos , Zhang Yu , Arias Andrés A. , Bailey Rasheed , Schlüter Agatha , Milisavljevic Baptiste , Bigio Benedetta , Le Voyer Tom , Materna Marie , Gervais Adrian , Moncada-Velez Marcela , Pala Francesca , Lazarov Tomi , Levy Romain , Neehus Anna-Lena , Rosain Jérémie , Peel Jessica , Chan Yi-Hao , Morin Marie-Paule , Pino-Ramirez Rosa Maria , Belkaya Serkan , Lorenzo Lazaro , Anton Jordi , Delafontaine Selket , Toubiana Julie , Bajolle Fanny , Fumadó Victoria , DeDiego Marta L. , Fidouh Nadhira , Rozenberg Flore , Pérez-Tur Jordi , Chen Shuibing , Evans Todd , Geissmann Frédéric , Lebon Pierre , Weiss Susan R. , Bonnet Damien , Duval Xavier ,   CoV-Contact Cohort§,   COVID Human Genetic Effort¶, Pan-Hammarström Qiang , Planas Anna M. , Meyts Isabelle , Haerynck Filomeen , Pujol Aurora , Sancho-Shimizu Vanessa , Dalgard Clifford L. , Bustamante Jacinta , Puel Anne , Boisson-Dupuis Stéphanie , Boisson Bertrand , Maniatis Tom , Zhang Qian , Bastard Paul , Notarangelo Luigi , Béziat Vivien , Perez de Diego Rebeca , Rodriguez-Gallego Carlos , Su Helen C. , Lifton Richard P. , Jouanguy Emmanuelle , Cobat Aurélie , Alsina Laia , Keles Sevgi , Haddad Elie , Abel Laurent , Belot Alexandre , Quintana-Murci Lluis , Rice Charles M. , Silverman Robert H. , Zhang Shen-Ying , Casanova Jean-Laurent , Alavoine Loubna , Behillil Sylvie , Burdet Charles , Charpentier Charlotte , Dechanet Aline , Descamps Diane , Duval Xavier , Ecobichon Jean-Luc , Enouf Vincent , Frezouls Wahiba , Houhou Nadhira , Kafif Ouifiya , Lehacaut Jonathan , Letrou Sophie , Lina Bruno , Lucet Jean-Christophe , Manchon Pauline , Nouroudine Mariama , Piquard Valentine , Quintin Caroline , Thy Michael , Tubiana Sarah , van der Werf Sylvie , Vignali Valérie , Visseaux Benoit , Yazdanpanah Yazdan , Chahine Abir , Waucquier Nawal , Migaud Maria-Claire , Deplanque Dominique , Djossou Félix , Mergeay-Fabre Mayka , Lucarelli Aude , Demar Magalie , Bruneau Léa , Gérardin Patrick , Maillot Adrien , Payet Christine , Laviolle Bruno , Laine Fabrice , Paris Christophe , Desille-Dugast Mireille , Fouchard Julie , Malvy Denis , Nguyen Duc , Pistone Thierry , Perreau Pauline , Gissot Valérie , Le Goas Carole , Montagne Samatha , Richard Lucie , Chirouze Catherine , Bouiller Kévin , Desmarets Maxime , Meunier Alexandre , Lefèvre Benjamin , Jeulin Hélène , Legrand Karine , Lomazzi Sandra , Tardy Bernard , Gagneux-Brunon Amandine , Bertholon Frédérique , Botelho-Nevers Elisabeth , Christelle Kouakam , Nicolas Leturque , Roufai Layidé , Amat Karine , Couffin-Cadiergues Sandrine , Espérou Hélène , Hendou Samia , Abel Laurent , Abolhassani Hassan , Aguilera-Albesa Sergio , Aiuti Alessandro , Akcan Ozge Metin , Akcay Nihal , Alkan Gulsum , Alkhater Suzan A. , Allende Luis Miguel , Alper Yosunkaya , Amenzoui Naima , Anderson Mark S. , Arkin Lisa , Aubart Melodie , Avramenko Iryna , Aydemir Şehnaz , Gayretli Aydin Zeynep Gökçe , Aytekin Caner , Aytekin Gökhan , Erol Aytekin Selma , Bando Silvia Yumi , Beland Kathie , Belkaya Serkan , Biggs Catherine M. , Bilbao Aburto Agurtzane , Blanchard-Rohner Geraldine , Blázquez-Gamero Daniel , Bloomfield Marketa , Bogunovic Dusan , Bondarenko Anastasia , Borghesi Alessandro , Bousfiha Amed Aziz , Boyarchuk Oksana , Brodin Petter , Bryceson Yenan , Bucciol Giorgia , Calcaterra Valeria , Casari Giorgio , Cavalcanti Andre , Celik Jale Bengi , Chrousos George P. , Colobran Roger , Condino-Neto Antonio , Conti Francesca , Cooper Megan , Coskuner Taner , Cyrus Cyril , D’Auria Enza , Delafontaine Selket , Drolet Beth A. , Bursal Duramaz Burcu , El Zein Loubna , Elnagdy Marwa H. , Emiroglu Melike , Erdeniz Emine Hafize , Fabi Marianna , Baris Feldman Hagit , Fellay Jacques , Fencl Filip , Filippatos Filippos , Freiss Julie , Fremuth Jiri , Gagro Alenka , Garcia-Solis Blanca , Vergine Gianluca , González-Montelongo Rafaela , Gul Yahya , Gülhan Belgin , Gultekin Sara Sebnem Kilic , Gut Marta , Halwani Rabih , Hammarström Lennart , Hatipoğlu Nevin , Heath James , Henrickson Sarah E. , Hernandez-Brito Elisa , Hoffman Ilse , Hoste Levi , Hsieh Elena , Íñigo-Campos Antonio , Itan Yuval , Jabandziev Petr , Kandemir Bahar , Kanık-Yüksek Saliha , Kapakli Hasan , Karbuz Adem , Kasapcopur Ozgur , Kechiche Robin , Kendir Demirkol Yasemin , Kilic Omer , Hansen Stella Kim , Klocperk Adam , Lau Yu-Lung , Lebl Jan , Lorenzo-Salazar José M. , Lucas Carrie L. , Maglorius Majistor , Marque Laura , Novoa Medina Yeray , Montesdeoca Melián Abián , Mentis Alexios-Fotios A. , Pato Michele T. , Michos Athanasios , Milner Joshua D. , Mogensen Trine H. , Muñoz-Barrera Adrián , Nepesov Serdar , Farela Neves João , Ng Ashley , Ng Lisa F. P. , Novelli Antonio , Novelli Giuseppe , Oz Fatma Nur , Ocejo-Viñals J. Gonzalo , Okada Satoshi , Orbak Zerrin , Kilic Ahmet Osman , Ouair Hind , Öz Şadiye Kübra Tüter , Özçelik Tayfun , Özkan Esra Akyüz , Parlakay Aslınur Özkaya , Pato Carlos N. , Paz-Artal Estela , Pelham Simon , Pellier Isabelle , Philippot Quentin , Planas-Serra Laura , Plassart Samira , Pokorna Petra , Polat Meltem , Poli Cecilia , Prando Carolina , Renia Laurent , Rivière Jacques G. , Rodríguez-Palmero Agustí , Roussel Lucie , Rubio-Rodriguez Luis A. , Salifu Moro , Sasek Lumir , Sasia Laura , Scherbina Anna , Schmitt Erica , Sediva Anna , Sevketoglu Esra , Slaba Katerina , Slaby Ondrej , Sobh Ali , Solé-Violán Jordi , Soler-Palacin Pere , De Somer Lien , Sözeri Betül , Spaan András N. , Stepanovskiy Yuriy , Tangye Stuart G. , Tanir Gonul , Tatsi Elizabeth Barbara , Thorball Christian W. , Hancerli Torun Selda , Turvey Stuart , Uddin Mohammed J. , Uyar Emel , Valencia-Ramos Juan , Van Den Rym Ana Maria , Vatansev Hulya , Castillo de Vera Martín , Vermeulen François , Vinh Donald C. , Volokha Alla , von Bernuth Horst , Wouters Carine , Yahşi Aysun , Yarar Volkan , Yesilbas Osman , Yıldız Mehmet , Zatz Mayana , Zawadzki Pawel , Zuccotti Gianvincenzo , Zhang Shen-Ying , Casanova Jean-Laurent 
Published: December 2022

Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of
OAS1
,
OAS2
, or
RNASEL
in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)–sensing OAS1 and OAS2 generate 2′-5′-linked oligoadenylates (2-5A) that activate the single-stranded RNA–degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L–deficient cells. Cytokine production in RNase L–deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS–RNase L deficiencies in these patients unleash the production of SARS-CoV-2–triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.