Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease

• Type of Material: Article
• Authors: Mehul Sharma, University of British Columbia; Daniel Leung, The University of Hong Kong; Mana Momenilandi, Necker Hospital for Sick Children; Lauren CW Jones, The University of British Columbia; Lucia Pacillo, Università degli Studi di Roma "Tor Vergata"; Alyssa E James, National Institute of Allergy and Infectious Diseases (NIAID); Jill R Murrell, The Children's Hospital of Philadelphia; Selket Delafontaine, Departement Microbiologie, Immunologie en Transplantatie; Jesmeen Maimaris, University College London; Maryam Vaseghi-Shanjani, The University of British Columbia; Kate L Del Bel, The University of British Columbia; Henry Y Lu, Harvard Medical School; Gilbert T Chua, The University of Hong Kong; Sillvia Di Cesare, Università degli Studi di Roma "Tor Vergata"; Oriol Fornes, BC Children's Hospital Research Institute; Zhongyi Liu, The University of Hong Kong; Gigliola Di Matteo, IRCCS Ospedale Pediatrico Bambino Gesù; Magie P Fu, The University of British Columbia; Donato Amodio, IRCCS Ospedale Pediatrico Bambino Gesù; Issan Yee San Tam, The University of Hong Kong; Gavin SW Chan, Queen Mary Hospital Hong Kong; Ashish Sharma, Emory University; Joshua Dalmann, The University of British Columbia; Robin Van Der Lee, BC Children's Hospital Research Institute; Géraldine Blanchard-Rohner, The University of British Columbia; Susan Lin, The University of British Columbia; Quentin Philippot, Hôpital Necker Enfants Malades; Philip A Richmond, The University of British Columbia; Jessica J Lee, BC Children's Hospital Research Institute; Allison Matthews, BC Children's Hospital Research Institute; Michael Seear, The University of British Columbia; Alexandra K Turvey, The University of British Columbia; Racheal L Philips, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Terri F Brown-Whitehorn, The Children's Hospital of Philadelphia; Chrsitopher J Gray, The Children's Hospital of Philadelphia; Kosuke Izumi, The Children's Hospital of Philadelphia; James R Treat, University of Pennsylvania Perelman School of Medicine; Kathleen H Wood, The Children's Hospital of Philadelphia; Justin Lack, National Institute of Allergy and Infectious Diseases (NIAID); Asya Khleborodova, National Institute of Allergy and Infectious Diseases (NIAID); Julie E Niemela, NIH Clinical Center (CC); Xingtian Yang, The University of Hong Kong; Rui Liang, The University of Hong Kong; Lin Kui, The University of Hong Kong; Christine Sze Man Wong, The University of Hong Kong; Grace Wing Kit Poon, Queen Mary Hospital Hong Kong; Alexander Hoischen, Radboud University Medical Center; Caspar I Van Der Made, Radboud University Medical Center; Jing Yang, The University of Hong Kong; Koon Wing Chan, The University of Hong Kong; Jaime Sou Da Rosa Duque, The University of Hong Kong; Pamela Pui Wah Lee, The University of Hong Kong; Marco Hok Kung Ho, The University of Hong Kong; Brian Hon Yin Chung, The University of Hong Kong; Huong Thi Minh Le, Center for Gastroenterology - Hepatobiliary - Urology - Vinmec Times City International Hospital; Wanling Yang, The University of Hong Kong; Pejman Rohani, Children's Medical Center (TUMS); Ali Fouladvand, Lorestan University of Medical Sciences; Hassan Rokni-Zadeh, School of Medicine, Zanjan University of Medical Sciences (ZUMS); Majid Changi-Ashtiani, Iranian Research Institute for Fundamental Sciences; Mohammad Miryounesi, SBUMS School of Medicine; Anne Puel, Hôpital Necker Enfants Malades; Mohammad Shahrooei, Departement Microbiologie, Immunologie en Transplantatie; Andrea Finocchi, Università degli Studi di Roma "Tor Vergata"; Paolo Rossi, Università degli Studi di Roma "Tor Vergata"; Beatrice Rivalta, Università degli Studi di Roma "Tor Vergata"; Cristina Cifaldi, IRCCS Ospedale Pediatrico Bambino Gesù; Antonio Novelli, IRCCS Ospedale Pediatrico Bambino Gesù; Chiara Passarelli, IRCCS Ospedale Pediatrico Bambino Gesù; Stefania Arasi, IRCCS Ospedale Pediatrico Bambino Gesù; Dominique Bullens, Departement Microbiologie, Immunologie en Transplantatie; Kate Sauer, Pediatric Pulmonology Division; Tania Claeys, Pediatric Gastroenterology Division; Catherine M Biggs, The University of British Columbia; Emma C Morris, University College London; Sergio D Rosenzweig, NIH Clinical Center (CC); John J O Shea, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Wyeth W Wasserman, BC Children's Hospital Research Institute; Melanie H Bedford, University of Toronto; Clara DM Van Karnebeek, BC Children's Hospital Research Institute; Paolo Palma, Università degli Studi di Roma "Tor Vergata"; Siobhan O Burns, University College London; Isabelle Meyts, Departement Microbiologie, Immunologie en Transplantatie; Jean-Laurent Casanova, Hôpital Necker Enfants Malades; Jonathan J Lyons, National Institute of Allergy and Infectious Diseases (NIAID); Nima Parvaneh, Children's Medical Center (TUMS); Anh Thi Van Nguyen, Vietnam National Children's Hospital; Caterina Cancrini, Università degli Studi di Roma "Tor Vergata"; Jennifer Heimall, The Children's Hospital of Philadelphia; Hanan Ahmed, McMaster University, Faculty of Health Sciences; Margaret L McKinnon, The University of British Columbia; Yu Lung Lau, The University of Hong Kong; Vivien Béziat, Hôpital Necker Enfants Malades; Stuart E Turvey, The University of British Columbia
• Language: English
• Date: 2023-05-01
• Publisher: Rockefeller University Press
• Publication Version: Final Published Version
• Copyright Statement: © 2023 Sharma et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1084/jem.20221755
• Title of Journal or Parent Work: Journal of Experimental Medicine
• Volume: 220
• Issue: 5
• Grant/Funding Information: J.S.D. Rosa Duque is supported by a donation in memory of Dr. Ton Lung Quong and Reverend Marion Quong. Z. Liu, R. Liang, and X. Yang are supported by the Edward and Yolanda Wong Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Additionally, the optimization of the Olink platform was supported by the PENTA Foundation, funded through an independent grant by ViiV Healthcare UK, named EPIICAL. Y.L. Lau is supported by the Society for the Relief of Disabled Children, Jeffrey Modell Foundation, Doris Zimmern Endowed Professorship in Community Child Health, and Chung Ko Lee and Cheung Yuen Kan Education and Research Fund. D. Leung is supported by the Croucher Foundation.; The work by J. Heimall was supported by the Elizabeth Paige Lavin Endowed Chair fund. This project has also been funded in part with federal funds from the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government; This work was supported by grants from the Canadian Institutes of Health Research (PJT 178054; S.E. Turvey), Genome British Columbia (SIP007; S.E. Turvey), and BC Children’s Hospital Foundation. S.E. Turvey holds a Tier 1 Canada Research Chair in Pediatric Precision Health and the Aubrey J. Tingle Professor of Pediatric Immunology. M. Sharma was supported by a CIHR Frederick Banting and Charles Best Canada Graduate Scholarships Doctoral Award and University of British Columbia Four Year Doctoral Fellowship (4YF). H.Y. Lu is supported by a Canada Graduate Scholarship, 4YF, Killam Doctoral Scholarship, Friedman Award for Scholars in Health, and a BC Children’s Hospital Research Institute Graduate Studentship. M. Vaseghi-Shanjani is funded by the Vanier Canada Graduate Scholarship and 4YF.; This work was also supported by Children’s Hospital Bambino Gesù, where L. Pacillo and B. Rivalta were supported by 4-yr doctoral scholarships. C. Cifaldi and C. Cancrini were supported by the Italian Ministry of Health; C. Cifaldi was supported with a 5x1000 Children’s Hospital post-doctoral scholarship, and C. Cancrini holds a Development of Innovative Diagnostic and Therapeutic Approaches for PID grant (Programma di rete, NET-2011-02350069) and Ricerca Corrente.; The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the French National Research Agency (ANR) under the “Investments for the Future” program (ANR-10-IAHU-01), ANR CARMIL2 (ANR-21-CE15-0034), Instituts Thématiques Multiorganismes (ITMO) Cancer of Aviesan, and Institut National du Cancer (INCa) within the framework of the 2021–2030 Cancer Control Strategy (on funds administered by the Institut National de la Santé et de la Recherche Médicale), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (EQU201903007798), the Square Foundation, Institut National de la Santé et de la Recherche Médicale, and Paris University Cité.
• Keywords: Asthma; Immunoglobulin E; Humans; Food Hypersensitivity; STAT6 Transcription Factor; Gain of Function Mutation
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Immunology

Abstract

STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti–IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder.