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

2023; Rockefeller University Press; Volume: 220; Issue: 5 Linguagem: Inglês

10.1084/jem.20221755

1540-9538

Mehul Sharma, Daniel Leung, Mana Momenilandi, Lauren C.W. Jones, Lucia Pacillo, Alyssa James, Jill R. Murrell, Selket Delafontaine, Jesmeen Maimaris, Maryam Vaseghi‐Shanjani, Kate L. Del Bel, Henry Y. Lu, Gilbert T. Chua, Silvia Di Cesare, Oriol Fornés, Zhongyi Liu, Gigliola Di Matteo, Maggie P. Fu, Donato Amodio, Issan Yee San Tam, Gavin S.W. Chan, Ashish Sharma, Joshua Dalmann, Robin van der Lee, 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 Gray, Kosuke Izumi, James R. Treat, Kathleen H. Wood, Justin Lack, Asya Khleborodova, Julie E. Niemela, Xingtian Yang, Rui Liang, Lin Kui, C. S. M. Wong, Grace Wing-kit Poon, Alexander Hoischen, Caspar I. van der Made, Jing Yang, Koon Wing Chan, Jaime S. Rosa Duque, Pamela Lee, M. 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 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 Casanova, Jonathan J. Lyons, Nima Parvaneh, Anh Thi Van Nguyen, Caterina Cancrini, Jennifer Heimall, Hanan Ahmed, Margaret L. McKinnon, YL Lau, Vivien Béziat, Stuart E. Turvey,

IL-33, ST2, and ILC Pathways

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.