Human germline heterozygous gain-of-function<i>STAT6</i>variants cause severe allergic disease
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- Mehul Sharma
- Dept. of Pediatrics, BC Children’s Hospital, University of British Columbia 1 , Vancouver, Canada
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- Daniel Leung
- Dept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong 2 , Hong Kong, China
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- Mana Momenilandi
- 3 , Paris, France
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- Lauren C.W. Jones
- Dept. of Pediatrics, BC Children’s Hospital, University of British Columbia 1 , Vancouver, Canada
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- Lucia Pacillo
- Dept. of System Medicine, Pediatric Chair, University of Tor Vergata 5 , Rome, Italy
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- Alyssa E. James
- Translational Allergic Immunopathology Unit, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), 8 , Bethesda, MD, USA
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- Jill R. Murrell
- Pathology and Laboratory Medicine, Division of Genomic Diagnostics, Children’s Hospital of Philadelphia 9 , Philadelphia, PA, USA
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- Selket Delafontaine
- Dept. of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, KU Leuven 10 , Leuven, Belgium
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- Jesmeen Maimaris
- Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London 12 , London, UK
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- Maryam Vaseghi-Shanjani
- Dept. of Pediatrics, BC Children’s Hospital, University of British Columbia 1 , Vancouver, Canada
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- Kate L. Del Bel
- Dept. of Pediatrics, BC Children’s Hospital, University of British Columbia 1 , Vancouver, Canada
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- Henry Y. Lu
- Division of Hematology/Oncology, Boston Children’s Hospital 14 , , Boston, MA, USA
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- Gilbert T. Chua
- Dept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong 2 , Hong Kong, China
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- Silvia Di Cesare
- Dept. of System Medicine, Pediatric Chair, University of Tor Vergata 5 , Rome, Italy
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- Oriol Fornes
- Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute 18 , Vancouver, Canada
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- Zhongyi Liu
- Dept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong 2 , Hong Kong, China
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- Gigliola Di Matteo
- Academic Dept. of Pediatrics (DPUO), 6 , Rome, Italy
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- Maggie P. Fu
- Dept. of Medical Genetics, The University of British Columbia 20 , Vancouver, Canada
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- Donato Amodio
- Academic Dept. of Pediatrics (DPUO), 6 , Rome, Italy
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- Issan Yee San Tam
- Dept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong 2 , Hong Kong, China
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- Gavin Shueng Wai Chan
- Dept. of Pathology, Queen Mary Hospital 22 , Hong Kong, China
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- Ashish A. Sharma
- Dept. of Pathology, Emory University 23 , Atlanta, GA, USA
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- Joshua Dalmann
- Dept. of Pediatrics, BC Children’s Hospital, University of British Columbia 1 , Vancouver, Canada
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- Robin van der Lee
- Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute 18 , Vancouver, Canada
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- Géraldine Blanchard-Rohner
- Dept. of Pediatrics, BC Children’s Hospital, University of British Columbia 1 , Vancouver, Canada
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- Susan Lin
- Dept. of Pediatrics, BC Children’s Hospital, University of British Columbia 1 , Vancouver, Canada
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- Quentin Philippot
- 3 , Paris, France
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- Phillip A. Richmond
- Dept. of Pediatrics, BC Children’s Hospital, University of British Columbia 1 , Vancouver, Canada
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- Jessica J. Lee
- Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute 18 , Vancouver, Canada
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- Allison Matthews
- Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute 18 , Vancouver, Canada
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- Michael Seear
- Dept. of Pediatrics, BC Children’s Hospital, University of British Columbia 1 , Vancouver, Canada
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- Alexandra K. Turvey
- Dept. of Pediatrics, BC Children’s Hospital, University of British Columbia 1 , Vancouver, Canada
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- Rachael L. Philips
- Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, NIH 27 , Bethesda, MD, USA
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- Terri F. Brown-Whitehorn
- Dept. of Pediatrics, Division of Allergy and Immunology, Children’s Hospital of Philadelphia 28 , Philadelphia, PA, USA
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- Christopher J. Gray
- Pediatrics, Division of Human Genetics, Children’s Hospital of Philadelphia 29 , Philadelphia, PA, USA
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- Kosuke Izumi
- Pediatrics, Division of Human Genetics, Children’s Hospital of Philadelphia 29 , Philadelphia, PA, USA
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- James R. Treat
- Pediatrics, Division of Pediatric Dermatology, Perelman School of Medicine, University of Pennsylvania 30 , Philadelphia, PA, USA
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- Kathleen H. Wood
- Pathology and Laboratory Medicine, Division of Genomic Diagnostics, Children’s Hospital of Philadelphia 9 , Philadelphia, PA, USA
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- Justin Lack
- NIAID Collaborative Bioinformatics Resource, NIAID 31 , , Bethesda, MD, USA
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- Asya Khleborodova
- NIAID Collaborative Bioinformatics Resource, NIAID 31 , , Bethesda, MD, USA
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- Julie E. Niemela
- Immunology Service, Clinical Center, NIH 32 , Bethesda, MD, USA
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- Xingtian Yang
- Dept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong 2 , Hong Kong, China
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- Rui Liang
- Dept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong 2 , Hong Kong, China
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- Lin Kui
- Dept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong 2 , Hong Kong, China
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- Christina Sze Man Wong
- Dept. of Medicine, Divison of Dermatology, The University of Hong Kong 34 , Hong Kong, China
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- Grace Wing Kit Poon
- Dept. of Paediatrics and Adolescent Medicine, Queen Mary Hospital 35 , Hong Kong, China
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- Alexander Hoischen
- Dept. of Human Genetics, Radboud University Medical Center 36 , Nijmegen, Netherlands
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- Caspar I. van der Made
- Dept. of Human Genetics, Radboud University Medical Center 36 , Nijmegen, Netherlands
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- Jing Yang
- Dept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong 2 , Hong Kong, China
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- Koon Wing Chan
- Dept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong 2 , Hong Kong, China
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- Jaime Sou Da Rosa Duque
- Dept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong 2 , Hong Kong, China
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- Pamela Pui Wah Lee
- Dept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong 2 , Hong Kong, China
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- Marco Hok Kung Ho
- Dept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong 2 , Hong Kong, China
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- Brian Hon Yin Chung
- Dept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong 2 , Hong Kong, China
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- Huong Thi Minh Le
- Pediatric Center, Vinmec Times City International General Hospital 38 , Hanoi, Vietnam
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- Wanling Yang
- Dept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong 2 , Hong Kong, China
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- Pejman Rohani
- Pediatrics, Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Centre of Excellence, Children’s Medical Center, University of Medical Sciences 39 , Tehran, Iran
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- Ali Fouladvand
- Pediatrics, Allergy and Clinical Immunology, Lorestan University of Medical Sciences 40 , Khoramabad, Iran
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- Hassan Rokni-Zadeh
- Dept. of Medical Biotechnology, School of Medicine, Zanjan University of Medical Sciences 41 , Zanjan, Iran
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- Majid Changi-Ashtiani
- School of Mathematics, Institute for Research in Fundamental Sciences 42 , Tehran, Iran
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- Mohammad Miryounesi
- Dept. of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences 43 , Tehran, Iran
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- Anne Puel
- 3 , Paris, France
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- Mohammad Shahrooei
- Microbiology and Immunology, Laboratory of Clinical Bacteriology and Mycology, KU Leuven 44 , Leuven, Belgium
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- Andrea Finocchi
- Dept. of System Medicine, Pediatric Chair, University of Tor Vergata 5 , Rome, Italy
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- Paolo Rossi
- Dept. of System Medicine, Pediatric Chair, University of Tor Vergata 5 , Rome, Italy
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- Beatrice Rivalta
- Dept. of System Medicine, Pediatric Chair, University of Tor Vergata 5 , Rome, Italy
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- Cristina Cifaldi
- Research Unit of Primary Immunodeficiency, 7 , Rome, Italy
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- Antonio Novelli
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children Hospital IRCCS 46 , Rome, Italy
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- Chiara Passarelli
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children Hospital IRCCS 46 , Rome, Italy
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- Stefania Arasi
- Allergy Unit, Area of Translational Research in Pediatric Specialities, Bambino Gesù Children’s Hospital, IRCCS 47 , Rome, Italy
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- Dominique Bullens
- Dept. of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven 48 , Leuven, Belgium
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- Kate Sauer
- Dept. of Pediatrics, Pediatric Pulmonology Division, AZ Sint-Jan Brugge 50 , Brugge, Belgium
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- Tania Claeys
- Dept. of Pediatrics, Pediatric Gastroenterology Division, AZ Sint-Jan Brugge 52 , Brugge, Belgium
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- Catherine M. Biggs
- Dept. of Pediatrics, BC Children’s Hospital, University of British Columbia 1 , Vancouver, Canada
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- Emma C. Morris
- Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London 12 , London, UK
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- Sergio D. Rosenzweig
- Immunology Service, Clinical Center, NIH 32 , Bethesda, MD, USA
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- John J. O’Shea
- Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, NIH 27 , Bethesda, MD, USA
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- Wyeth W. Wasserman
- Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute 18 , Vancouver, Canada
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- H. Melanie Bedford
- Dept. of Paediatrics, University of Toronto 26 , Toronto, Canada
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- Clara D.M. van Karnebeek
- Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute 18 , Vancouver, Canada
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- Paolo Palma
- Dept. of System Medicine, Pediatric Chair, University of Tor Vergata 5 , Rome, Italy
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- Siobhan O. Burns
- Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London 12 , London, UK
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- Isabelle Meyts
- Dept. of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, KU Leuven 10 , Leuven, Belgium
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- Jean-Laurent Casanova
- 3 , Paris, France
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- Jonathan J. Lyons
- Translational Allergic Immunopathology Unit, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), 8 , Bethesda, MD, USA
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- Nima Parvaneh
- 57 , Tehran, Iran
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- Anh Thi Van Nguyen
- Dept. of Immunology, Allergy and Rheumatology, Division of Primary Immunodeficiency, Vietnam National Children’s Hospital 58 , Hanoi, Vietnam
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- Caterina Cancrini
- Dept. of System Medicine, Pediatric Chair, University of Tor Vergata 5 , Rome, Italy
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- Jennifer Heimall
- Dept. of Pediatrics, Division of Allergy and Immunology, Children’s Hospital of Philadelphia 28 , Philadelphia, PA, USA
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- Hanan Ahmed
- Faculty of Health Sciences, McMaster University 59 , Hamilton, Canada
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- Margaret L. McKinnon
- Dept. of Medical Genetics, University of British Columbia 19 , Vancouver, Canada
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- Yu Lung Lau
- Dept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong 2 , Hong Kong, China
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- Vivien Béziat
- 3 , Paris, France
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- Stuart E. Turvey
- Dept. of Pediatrics, BC Children’s Hospital, University of British Columbia 1 , Vancouver, Canada
抄録
<jats:p>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.</jats:p>
収録刊行物
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- Journal of Experimental Medicine
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Journal of Experimental Medicine 220 (5), 2023-03-08
Rockefeller University Press