ArticleThe Journal of experimental medicine2023
Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease.
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Article in The Journal of experimental medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers, 3 of them syntheses that pooled it.
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65citing papers in PubMed, 3 pooled it
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65 citing papers in PubMed, 3 syntheses or guidelines pooled it.
- Biologics and JAK inhibitors for atopic manifestations in inborn errors of immunity: a systematic review.Frontiers in allergy · 2026Pooled it
- Italian pediatric experts' consensus statement on diagnosis and management of primary atopic disorders.Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology · 2025Guideline
- Atopic dermatitis and lymphoma risk: a systematic review and meta-analysis.Frontiers in oncology · 2025Pooled it
- Understanding the Variability of Peanut-Oral Immunotherapy Responses by Multi-Omics Profiling of Immune Cells.Allergy · 2025Trial
- Vascularized human skin assembloids model compartmental skin organization and immune responsiveness in vitro.Experimental & molecular medicine · 2026Article
- Emerging Paediatric Uses of Dupilumab Beyond Approvals.Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology · 2026Review
- Primary atopic disorders: Monogenic insights into immunity.Journal of human immunity · 2026Review
- Human germline biallelic loss-of-functionJournal of human immunity · 2026Article
- Hypogammaglobulinemia in Children with Atopic Dermatitis.Children (Basel, Switzerland) · 2026Article
- Oncostatin M receptor deficiency as a novel candidate genetic cause of autosomal recessive hyper-IgE syndrome.Journal of human immunity · 2026Article
- STAT6: Multidimensional analysis from hematopoietic immune regulation to pathogenesis mechanisms and therapeutic targets in hematologic malignancies.Annals of hematology · 2026Review
- Eosinophilic Esophagitis: Mechanisms of Disease and Approach to Treatment.Current allergy and asthma reports · 2026Review
- JAK-STAT signaling: molecular mechanism and targeted treatment in dento-maxillofacial abnormalities.International journal of oral science · 2026Review
- Pediatric IPEX-Associated Dermatitis Responds To Dupilumab: Evidence from Skin Transcriptomics and Immune Profiling.Journal of clinical immunology · 2026Article
- Heritability and Transcriptional Impact of JAK3, STAT5A and STAT6 Variants in a Tyrolean Family.International journal of molecular sciences · 2026Article
- Case Report: A case series of using whole exome sequencing to detect novel variants in Vietnamese patients with inborn errors of immunity.Frontiers in genetics · 2026Article
- The Multifaceted Roles of STAT6: Implications for Precision Immunotherapeutics.ImmunoTargets and therapy · 2026Review
- IL-4Rα antagonist (Stapokibart) in refractory palmoplantar pustulosis: a case report and literature review of Th2-targeted therapies.Frontiers in immunology · 2026Review
- CPA3 drives the development of asthma by promoting the activation of the JAK/STAT6 pathway.Respiratory research · 2025Article
- Rare germline JAK/STAT variants in a Korean cohort amplify innate immune responses to vaccination.iScience · 2025Article
5 more citing papers are in PubMed but not listed here.
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Authors and funding
94 authors.
Mehul Sharma *Dept. of Pediatrics, BC Children's Hospital, University of British Columbia , Vancouver, Canada.ORCID 0000-0002-9591-0415
Daniel Leung *Dept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong , Hong Kong, China.ORCID 0000-0002-9360-6233
Mana Momenilandi *Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker Hospital for Sick Children, Paris, France.ORCID 0000-0002-5340-2762
Lauren C W Jones *Dept. of Pediatrics, BC Children's Hospital, University of British Columbia , Vancouver, Canada.ORCID 0000-0002-8221-5712
Lucia Pacillo *Dept. of System Medicine, Pediatric Chair, University of Tor Vergata, Rome, Italy.ORCID 0000-0002-7950-8848
Alyssa E James *Translational Allergic Immunopathology Unit, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) , Bethesda, MD, USA.ORCID 0000-0001-9726-6611
Jill R Murrell *Pathology and Laboratory Medicine, Division of Genomic Diagnostics, Children's Hospital of Philadelphia , Philadelphia, PA, USA.ORCID 0000-0002-1885-8385
Selket Delafontaine *Dept. of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, KU Leuven , Leuven, Belgium.ORCID 0000-0002-8985-8155
Jesmeen Maimaris *Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London , London, UK.ORCID 0000-0003-4169-8209
Maryam Vaseghi-Shanjani *Dept. of Pediatrics, BC Children's Hospital, University of British Columbia , Vancouver, Canada.ORCID 0000-0001-8734-169X
Kate L Del Bel *Dept. of Pediatrics, BC Children's Hospital, University of British Columbia , Vancouver, Canada.ORCID 0000-0001-7669-9530
Henry Y Lu *Division of Hematology/Oncology, Boston Children's Hospital , Harvard Medical School, Boston, MA, USA.ORCID 0000-0002-1645-7748
Gilbert T ChuaDept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong , Hong Kong, China.ORCID 0000-0003-0333-0059
Silvia Di CesareDept. of System Medicine, Pediatric Chair, University of Tor Vergata, Rome, Italy.ORCID 0000-0002-9912-7997
Oriol FornesCentre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute , Vancouver, Canada.ORCID 0000-0002-5969-3054
Zhongyi LiuDept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong , Hong Kong, China.ORCID 0000-0002-5001-9186
Gigliola Di MatteoAcademic Dept. of Pediatrics (DPUO), Unit of Clinical Immunology and Vaccinology, IRCCS Bambin Gesù Children Hospital, Rome, Italy.ORCID 0000-0001-8344-5635
Maggie P FuDept. of Medical Genetics, The University of British Columbia , Vancouver, Canada.ORCID 0000-0002-7226-1096
Donato AmodioAcademic Dept. of Pediatrics (DPUO), Unit of Clinical Immunology and Vaccinology, IRCCS Bambin Gesù Children Hospital, Rome, Italy.ORCID 0000-0003-4550-3018
Issan Yee San TamDept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong , Hong Kong, China.ORCID 0000-0003-2152-8632
Gavin Shueng Wai ChanDept. of Pathology, Queen Mary Hospital , Hong Kong, China.ORCID 0000-0003-3504-5949
Ashish A SharmaDept. of Pathology, Emory University , Atlanta, GA, USA.ORCID 0000-0001-9444-7046
Joshua DalmannDept. of Pediatrics, BC Children's Hospital, University of British Columbia , Vancouver, Canada.ORCID 0000-0002-6450-0536
Robin van der LeeCentre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute , Vancouver, Canada.ORCID 0000-0001-7391-9438
Géraldine Blanchard-RohnerDept. of Pediatrics, BC Children's Hospital, University of British Columbia , Vancouver, Canada.ORCID 0000-0002-9974-2172
Susan LinDept. of Pediatrics, BC Children's Hospital, University of British Columbia , Vancouver, Canada.ORCID 0000-0003-4743-3180
Quentin PhilippotLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker Hospital for Sick Children, Paris, France.ORCID 0000-0003-3429-9605
Phillip A RichmondDept. of Pediatrics, BC Children's Hospital, University of British Columbia , Vancouver, Canada.ORCID 0000-0003-1882-6014
Jessica J LeeCentre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute , Vancouver, Canada.ORCID 0000-0002-6050-0731
Allison MatthewsCentre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute , Vancouver, Canada.ORCID 0000-0001-8394-0337
Michael SeearDept. of Pediatrics, BC Children's Hospital, University of British Columbia , Vancouver, Canada.ORCID 0000-0002-5899-7208
Alexandra K TurveyDept. of Pediatrics, BC Children's Hospital, University of British Columbia , Vancouver, Canada.ORCID 0000-0003-1945-7775
Rachael L PhilipsMolecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, NIH , Bethesda, MD, USA.ORCID 0000-0001-5440-4594
Terri F Brown-WhitehornDept. of Pediatrics, Division of Allergy and Immunology, Children's Hospital of Philadelphia , Philadelphia, PA, USA.ORCID 0000-0003-3950-8699
Christopher J GrayPediatrics, Division of Human Genetics, Children's Hospital of Philadelphia , Philadelphia, PA, USA.ORCID 0000-0002-7519-698X
Kosuke IzumiPediatrics, Division of Human Genetics, Children's Hospital of Philadelphia , Philadelphia, PA, USA.ORCID 0000-0002-7922-7480
James R TreatPediatrics, Division of Pediatric Dermatology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA.ORCID 0000-0001-9945-8713
Kathleen H WoodPathology and Laboratory Medicine, Division of Genomic Diagnostics, Children's Hospital of Philadelphia , Philadelphia, PA, USA.ORCID 0000-0001-6566-4885
Justin LackNIAID Collaborative Bioinformatics Resource, NIAID , NIH, Bethesda, MD, USA.ORCID 0000-0003-0584-4010
Asya KhleborodovaNIAID Collaborative Bioinformatics Resource, NIAID , NIH, Bethesda, MD, USA.ORCID 0000-0003-0118-4342
Julie E NiemelaImmunology Service, Clinical Center, NIH , Bethesda, MD, USA.ORCID 0000-0003-4197-3792
Xingtian YangDept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong , Hong Kong, China.ORCID 0000-0002-8849-0782
Rui LiangDept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong , Hong Kong, China.ORCID 0000-0003-2267-4885
Lin KuiDept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong , Hong Kong, China.ORCID 0000-0002-3349-0697
Christina Sze Man WongDept. of Medicine, Divison of Dermatology, The University of Hong Kong , Hong Kong, China.ORCID 0000-0003-4603-6407
Grace Wing Kit PoonDept. of Paediatrics and Adolescent Medicine, Queen Mary Hospital , Hong Kong, China.ORCID 0000-0001-5087-1478
Alexander HoischenDept. of Human Genetics, Radboud University Medical Center , Nijmegen, Netherlands.ORCID 0000-0002-8072-4476
Caspar I van der MadeDept. of Human Genetics, Radboud University Medical Center , Nijmegen, Netherlands.ORCID 0000-0003-0763-4017
Jing YangDept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong , Hong Kong, China.ORCID 0000-0002-2405-8990
Koon Wing ChanDept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong , Hong Kong, China.ORCID 0000-0001-9069-4568
Jaime Sou Da Rosa DuqueDept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong , Hong Kong, China.ORCID 0000-0002-5292-5510
Pamela Pui Wah LeeDept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong , Hong Kong, China.ORCID 0000-0002-5934-7338
Marco Hok Kung HoDept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong , Hong Kong, China.ORCID 0000-0003-1802-2120
Brian Hon Yin ChungDept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong , Hong Kong, China.ORCID 0000-0002-7044-5916
Huong Thi Minh LePediatric Center, Vinmec Times City International General Hospital , Hanoi, Vietnam.ORCID 0000-0002-7165-7259
Wanling YangDept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong , Hong Kong, China.ORCID 0000-0003-0063-6327
Pejman RohaniPediatrics, Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Centre of Excellence, Children's Medical Center, University of Medical Sciences , Tehran, Iran.ORCID 0000-0002-4208-8130
Ali FouladvandPediatrics, Allergy and Clinical Immunology, Lorestan University of Medical Sciences , Khoramabad, Iran.ORCID 0000-0002-5082-5735
Hassan Rokni-ZadehDept. of Medical Biotechnology, School of Medicine, Zanjan University of Medical Sciences , Zanjan, Iran.ORCID 0000-0001-5503-0344
Majid Changi-AshtianiSchool of Mathematics, Institute for Research in Fundamental Sciences , Tehran, Iran.ORCID 0000-0001-6428-9323
Mohammad MiryounesiDept. of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences , Tehran, Iran.ORCID 0000-0003-4705-3794
Anne PuelLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker Hospital for Sick Children, Paris, France.ORCID 0000-0003-2603-0323
Mohammad ShahrooeiMicrobiology and Immunology, Laboratory of Clinical Bacteriology and Mycology, KU Leuven , Leuven, Belgium.ORCID 0000-0002-4974-3441
Andrea FinocchiDept. of System Medicine, Pediatric Chair, University of Tor Vergata, Rome, Italy.ORCID 0000-0003-0958-8536
Paolo RossiDept. of System Medicine, Pediatric Chair, University of Tor Vergata, Rome, Italy.ORCID 0000-0003-2620-7918
Beatrice RivaltaDept. of System Medicine, Pediatric Chair, University of Tor Vergata, Rome, Italy.ORCID 0000-0003-2199-289X
Cristina CifaldiResearch Unit of Primary Immunodeficiency, IRCCS Bambin Gesù Children Hospital, Rome, Italy.ORCID 0000-0002-7170-7279
Antonio NovelliLaboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children Hospital IRCCS , Rome, Italy.ORCID 0000-0002-9037-4297
Chiara PassarelliLaboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children Hospital IRCCS , Rome, Italy.ORCID 0000-0001-7919-4626
Stefania ArasiAllergy Unit, Area of Translational Research in Pediatric Specialities, Bambino Gesù Children's Hospital, IRCCS , Rome, Italy.ORCID 0000-0002-8135-0568
Dominique BullensDept. of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven , Leuven, Belgium.ORCID 0000-0002-4595-9579
Kate SauerDept. of Pediatrics, Pediatric Pulmonology Division, AZ Sint-Jan Brugge , Brugge, Belgium.ORCID 0000-0002-4523-7832
Tania ClaeysDept. of Pediatrics, Pediatric Gastroenterology Division, AZ Sint-Jan Brugge , Brugge, Belgium.ORCID 0000-0001-8096-5774
Catherine M BiggsDept. of Pediatrics, BC Children's Hospital, University of British Columbia , Vancouver, Canada.ORCID 0000-0002-4363-2660
Emma C MorrisInstitute of Immunity and Transplantation, Division of Infection and Immunity, University College London , London, UK.ORCID 0000-0003-4834-1130
Sergio D RosenzweigImmunology Service, Clinical Center, NIH , Bethesda, MD, USA.ORCID 0000-0002-5550-9678
John J O'SheaMolecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, NIH , Bethesda, MD, USA.
Wyeth W WassermanCentre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute , Vancouver, Canada.ORCID 0000-0001-6098-6412
H Melanie BedfordDept. of Paediatrics, University of Toronto , Toronto, Canada.ORCID 0000-0002-2932-5621
Clara D M van KarnebeekCentre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute , Vancouver, Canada.ORCID 0000-0002-2648-8337
Paolo PalmaDept. of System Medicine, Pediatric Chair, University of Tor Vergata, Rome, Italy.ORCID 0000-0002-3066-4719
Siobhan O Burns *Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London , London, UK.
Isabelle Meyts *Dept. of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, KU Leuven , Leuven, Belgium.ORCID 0000-0003-1214-0302
Jean-Laurent Casanova *Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker Hospital for Sick Children, Paris, France.ORCID 0000-0002-7782-4169
Jonathan J Lyons *Translational Allergic Immunopathology Unit, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) , Bethesda, MD, USA.ORCID 0000-0002-2346-8189
Nima Parvaneh *Department of Pediatrics, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.ORCID 0000-0002-3397-9716
Anh Thi Van Nguyen *Dept. of Immunology, Allergy and Rheumatology, Division of Primary Immunodeficiency, Vietnam National Children's Hospital , Hanoi, Vietnam.ORCID 0000-0003-4163-466X
Caterina Cancrini *Dept. of System Medicine, Pediatric Chair, University of Tor Vergata, Rome, Italy.ORCID 0000-0001-8410-9617
Jennifer Heimall *Dept. of Pediatrics, Division of Allergy and Immunology, Children's Hospital of Philadelphia , Philadelphia, PA, USA.ORCID 0000-0001-7939-5102
Hanan Ahmed *Faculty of Health Sciences, McMaster University , Hamilton, Canada.ORCID 0000-0003-0854-9244
Margaret L McKinnon *Dept. of Medical Genetics, University of British Columbia , Vancouver, Canada.ORCID 0000-0002-3161-414X
Yu Lung Lau *Dept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong , Hong Kong, China.ORCID 0000-0002-4780-0289
Vivien Béziat *Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker Hospital for Sick Children, Paris, France.ORCID 0000-0002-4020-824X
Stuart E Turvey *Dept. of Pediatrics, BC Children's Hospital, University of British Columbia , Vancouver, Canada.ORCID 0000-0003-1599-1065
Funding
Infectious Diseases Research Technologies Core - BethesdaZICAI001051 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI CHERRY, JAMES · 2009 to 2025
$226.1MStat transcription factors in immunoregulation and autoimmune diseaseZIAAR041159 · NIAMS · NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES · PI O'SHEA, JOHN · 2009 to 2025
$49.3MStudies of Inherited Causes of Fungal SusceptabilityZIAAI001122 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI ROSENZWEIG, SERGIO · 2010 to 2025
$26.0MTranslational studies in allergic reactions and inflammationZIAAI001192 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI LYONS, JONATHAN · 2014 to 2023
$12.7MTargeting Janus kinases in the treatment of autoimmune diseaseZIAAR041106 · NIAMS · NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES · PI O'SHEA, JOHN · 2009 to 2024
$4.8MGenome-wide search for inborn errors of IL-17 immunity underlying chronic mucocutaneous candidiasisR01AI127564 · NIAID · UT SOUTHWESTERN MEDICAL CENTER · PI Jean-Laurent Casanova · 2017 to 2026
$4.8MMutation Analysis Of Selected Lymphoid Immune DisordersZIACL010304 · CLC · CLINICAL CENTER · PI ROSENZWEIG, SERGIO · 2009 to 2025
$0kHoward Hughes Medical InstituteNIAID NIH HHS R01 AI127564
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.
Indexed as
AsthmaFood HypersensitivityGain of Function MutationHumansImmunoglobulin ESTAT6 Transcription FactorImmunoglobulin ESTAT6 protein, humanSTAT6 Transcription Factor
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