Article Dans Une Revue Journal of Experimental Medicine Année : 2023

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

Mehul Sharma , Daniel Leung (1) , Mana Momenilandi , Lauren C.W. Jones , Lucia Pacillo , Alyssa E James , Jill R Murrell (2) , Selket Delafontaine , Jesmeen Maimaris , Maryam Vaseghi-Shanjani , Kate L del Bel , Henry Y Lu , Gilbert T Chua , Silvia Di Cesare (3) , Oriol Fornes (4) , Zhongyi Liu , Gigliola Di Matteo , Maggie P Fu , Donato Amodio , Issan Yee San Tam , Gavin Shueng Wai Chan , Ashish A Sharma , Joshua Dalmann , Robin van der Lee (5) , Géraldine Blanchard-Rohner , Susan Lin , Quentin Philippot , Phillip A Richmond , Jessica J Lee , Allison Matthews , Michael Seear , Alexandra K Turvey , Rachael L Philips , Terri F Brown-Whitehorn , Christopher J Gray , Kosuke Izumi , James R Treat , Kathleen H Wood , Justin Lack , Asya Khleborodova , Julie E Niemela , Xingtian Yang , Rui Liang , Lin Kui , Christina Sze Man Wong , Grace Wing Kit Poon , Alexander Hoischen , Caspar I van der Made , Jing Yang , Koon Wing Chan , Jaime Sou Da Rosa Duque , Pamela Pui Wah Lee , Marco Hok Kung Ho , Brian Hon Yin Chung , Huong Thi Minh Le , Wanling Yang , Pejman Rohani , Ali Fouladvand , Hassan Rokni-Zadeh , Majid Changi-Ashtiani , Mohammad Miryounesi , Anne Puel , Mohammad Shahrooei , Andrea Finocchi , Paolo Rossi , Beatrice Rivalta , Cristina Cifaldi , Antonio Novelli , Chiara Passarelli , Stefania Arasi , Dominique Bullens , Kate Sauer , Tania Claeys , Catherine M Biggs , Emma C Morris , Sergio D Rosenzweig , John J O’shea , Wyeth W Wasserman , H. Melanie Bedford , Clara D.M. van Karnebeek , Paolo Palma , Siobhan O Burns , Isabelle Meyts , Jean-Laurent L Casanova , Jonathan J Lyons , Nima Parvaneh , Anh Thi Van Nguyen , Caterina Cancrini , Jennifer Heimall , Hanan Ahmed , Margaret L Mckinnon , Yu Lung Lau , Vivien Béziat (6, 7, 8, 9) , Stuart E Turvey
Mehul Sharma
Mana Momenilandi
Lauren C.W. Jones
Lucia Pacillo
Alyssa E James
Jill R Murrell
Selket Delafontaine
Jesmeen Maimaris
Maryam Vaseghi-Shanjani
Kate L del Bel
Henry Y Lu
Gilbert T Chua
Zhongyi Liu
Gigliola Di Matteo
Maggie P Fu
Donato Amodio
Issan Yee San Tam
Gavin Shueng Wai Chan
Ashish A Sharma
Joshua Dalmann
Géraldine Blanchard-Rohner
Susan Lin
Quentin Philippot
Phillip A Richmond
Jessica J Lee
Allison Matthews
Michael Seear
Alexandra K Turvey
Rachael L Philips
Terri F Brown-Whitehorn
Christopher J Gray
Kosuke Izumi
James R Treat
Kathleen H Wood
Justin Lack
Asya Khleborodova
Julie E Niemela
Xingtian Yang
Rui Liang
Lin Kui
Christina Sze Man Wong
Grace Wing Kit Poon
Alexander Hoischen
Caspar I van der Made
Jing Yang
Koon Wing Chan
Jaime Sou Da Rosa Duque
Pamela Pui Wah Lee
Marco Hok Kung Ho
Brian Hon Yin Chung
Huong Thi Minh Le
Wanling Yang
Pejman Rohani
Ali Fouladvand
Hassan Rokni-Zadeh
Majid Changi-Ashtiani
Mohammad Miryounesi
Anne Puel
Mohammad Shahrooei
Andrea Finocchi
Paolo Rossi
Beatrice Rivalta
Cristina Cifaldi
Antonio Novelli
Chiara Passarelli
Stefania Arasi
Dominique Bullens
Kate Sauer
Tania Claeys
Catherine M Biggs
Emma C Morris
Sergio D Rosenzweig
John J O’shea
  • Fonction : Auteur
Wyeth W Wasserman
H. Melanie Bedford
Clara D.M. van Karnebeek
Paolo Palma
Siobhan O Burns
  • Fonction : Auteur
Isabelle Meyts
Jean-Laurent L Casanova
Jonathan J Lyons
Nima Parvaneh
Anh Thi Van Nguyen
Caterina Cancrini
Jennifer Heimall
Hanan Ahmed
Margaret L Mckinnon
Yu Lung Lau
Stuart E Turvey

Résumé

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.

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Dates et versions

hal-04876411 , version 1 (09-01-2025)

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Mehul Sharma, Daniel Leung, Mana Momenilandi, Lauren C.W. Jones, Lucia Pacillo, et al.. Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease. Journal of Experimental Medicine, 2023, 220 (5), ⟨10.1084/jem.20221755⟩. ⟨hal-04876411⟩
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