Human germline heterozygous gain-of-function<i>STAT6</i>variants cause severe allergic disease-Reference-Cited by-同舟云学术

Human germline heterozygous gain-of-functionSTAT6variants cause severe allergic disease

Published:2023-03-08 Issue:5 Volume:220 Page:
ISSN:0022-1007
Container-title:Journal of Experimental Medicine
language:en
Short-container-title:

Author:

Sharma Mehul¹^ORCID,Leung Daniel²^ORCID,Momenilandi Mana³⁴⁵^ORCID,Jones Lauren C.W.¹^ORCID,Pacillo Lucia⁶⁷⁸⁹¹⁰¹¹^ORCID,James Alyssa E.¹²¹³^ORCID,Murrell Jill R.¹⁴^ORCID,Delafontaine Selket¹⁵¹⁶^ORCID,Maimaris Jesmeen¹⁷¹⁸^ORCID,Vaseghi-Shanjani Maryam¹^ORCID,Del Bel Kate L.¹^ORCID,Lu Henry Y.¹⁹²⁰²¹²²^ORCID,Chua Gilbert T.²²³^ORCID,Di Cesare Silvia⁶¹⁰¹¹^ORCID,Fornes Oriol²⁴²⁵^ORCID,Liu Zhongyi²^ORCID,Di Matteo Gigliola⁷⁸⁹¹⁰¹¹^ORCID,Fu Maggie P.²⁶²⁷^ORCID,Amodio Donato⁷⁸⁹^ORCID,Tam Issan Yee San²^ORCID,Chan Gavin Shueng Wai²⁸^ORCID,Sharma Ashish A.²⁹^ORCID,Dalmann Joshua¹^ORCID,van der Lee Robin²⁴²⁵^ORCID,Blanchard-Rohner Géraldine¹³⁰^ORCID,Lin Susan¹^ORCID,Philippot Quentin³⁴⁵^ORCID,Richmond Phillip A.¹²⁴^ORCID,Lee Jessica J.²⁴³¹^ORCID,Matthews Allison²⁴³²^ORCID,Seear Michael¹^ORCID,Turvey Alexandra K.¹^ORCID,Philips Rachael L.³³^ORCID,Brown-Whitehorn Terri F.³⁴^ORCID,Gray Christopher J.³⁵^ORCID,Izumi Kosuke³⁵^ORCID,Treat James R.³⁶^ORCID,Wood Kathleen H.¹⁴^ORCID,Lack Justin³⁷³⁸^ORCID,Khleborodova Asya³⁷³⁸^ORCID,Niemela Julie E.³⁹^ORCID,Yang Xingtian²^ORCID,Liang Rui²^ORCID,Kui Lin²⁴⁰^ORCID,Wong Christina Sze Man⁴¹^ORCID,Poon Grace Wing Kit⁴²^ORCID,Hoischen Alexander⁴³^ORCID,van der Made Caspar I.⁴³^ORCID,Yang Jing²^ORCID,Chan Koon Wing²^ORCID,Rosa Duque Jaime Sou Da²^ORCID,Lee Pamela Pui Wah²^ORCID,Ho Marco Hok Kung²⁴⁴^ORCID,Chung Brian Hon Yin²^ORCID,Le Huong Thi Minh⁴⁵^ORCID,Yang Wanling²^ORCID,Rohani Pejman⁴⁶^ORCID,Fouladvand Ali⁴⁷^ORCID,Rokni-Zadeh Hassan⁴⁸^ORCID,Changi-Ashtiani Majid⁴⁹^ORCID,Miryounesi Mohammad⁵⁰^ORCID,Puel Anne³⁴⁵⁵¹⁵²⁵³⁵⁴^ORCID,Shahrooei Mohammad⁵⁵^ORCID,Finocchi Andrea⁶¹⁰¹¹^ORCID,Rossi Paolo⁶⁵⁶^ORCID,Rivalta Beatrice⁶⁷⁸⁹¹⁰¹¹^ORCID,Cifaldi Cristina¹⁰¹¹^ORCID,Novelli Antonio⁵⁷^ORCID,Passarelli Chiara⁵⁷^ORCID,Arasi Stefania⁵⁸^ORCID,Bullens Dominique⁵⁹⁶⁰^ORCID,Sauer Kate⁶¹⁶²^ORCID,Claeys Tania⁶³^ORCID,Biggs Catherine M.¹^ORCID,Morris Emma C.¹⁷¹⁸^ORCID,Rosenzweig Sergio D.³⁹^ORCID,O’Shea John J.³³,Wasserman Wyeth W.²⁴^ORCID,Bedford H. Melanie³²⁶⁴^ORCID,van Karnebeek Clara D.M.²⁴⁶⁵^ORCID,Palma Paolo⁶⁷⁸⁹^ORCID,Burns Siobhan O.¹⁷¹⁸,Meyts Isabelle¹⁵¹⁶^ORCID,Casanova Jean-Laurent³⁴⁵⁶⁶⁶⁷⁶⁸⁶⁹⁵¹⁵²⁵³⁵⁴^ORCID,Lyons Jonathan J.¹²¹³^ORCID,Parvaneh Nima⁷⁰⁷¹⁷²⁷³^ORCID,Nguyen Anh Thi Van⁷⁴^ORCID,Cancrini Caterina⁶¹⁰¹¹^ORCID,Heimall Jennifer³⁴^ORCID,Ahmed Hanan⁷⁵^ORCID,McKinnon Margaret L.²⁵^ORCID,Lau Yu Lung²^ORCID,Béziat Vivien³⁴⁵⁵¹⁵²⁵³⁵⁴^ORCID,Turvey Stuart E.¹^ORCID

Affiliation:

1. Dept. of Pediatrics, BC Children’s Hospital, University of British Columbia 1 , Vancouver, Canada

2. Dept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong 2 , Hong Kong, China

3. 3 , Paris, France

4. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker Hospital for Sick Children 3 , Paris, France

5. Imagine Institute, University of Paris-Cité 4 , Paris, France

6. Dept. of System Medicine, Pediatric Chair, University of Tor Vergata 5 , Rome, Italy

7. Academic Dept. of Pediatrics (DPUO), 6 , Rome, Italy

8. Unit of Clinical Immunology and Vaccinology, 6 , Rome, Italy

9. IRCCS Bambin Gesù Children Hospital 6 , Rome, Italy

10. Research Unit of Primary Immunodeficiency, 7 , Rome, Italy

11. IRCCS Bambin Gesù Children Hospital 7 , Rome, Italy

12. Translational Allergic Immunopathology Unit, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), 8 , Bethesda, MD, USA

13. National Institutes of Health (NIH) 8 , Bethesda, MD, USA

14. Pathology and Laboratory Medicine, Division of Genomic Diagnostics, Children’s Hospital of Philadelphia 9 , Philadelphia, PA, USA

15. Dept. of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, KU Leuven 10 , Leuven, Belgium

16. Dept. of Pediatrics, Pediatric Immunodeficiencies Division, University Hospitals Leuven 11 , Leuven, Belgium

17. Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London 12 , London, UK

18. Dept. of Immunology, Royal Free London NHS Foundation Trust 13 , London, UK

19. Division of Hematology/Oncology, Boston Children’s Hospital 14 , , Boston, MA, USA

20. Harvard Medical School 14 , , Boston, MA, USA

21. Dept. of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School 15 , Boston, MA, USA

22. Broad Institute of Massachusetts Institute of Technology and Harvard 16 , Cambridge, MA, USA

23. Allergy Centre, Union Hospital 17 , Hong Kong, China

24. Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute 18 , Vancouver, Canada

25. Dept. of Medical Genetics, University of British Columbia 19 , Vancouver, Canada

26. Dept. of Medical Genetics, The University of British Columbia 20 , Vancouver, Canada

27. Genome Science and Technology Program, Faculty of Science, The University of British Columbia 21 , Vancouver, Canada

28. Dept. of Pathology, Queen Mary Hospital 22 , Hong Kong, China

29. Dept. of Pathology, Emory University 23 , Atlanta, GA, USA

30. Unit of Immunology and Vaccinology, Division of General Pediatrics, Dept. of Woman, Child, and Adolescent Medicine, Geneva University Hospitals and Faculty of Medicine, University of Geneva 24 , Geneva, Switzerland

31. Genome Science and Technology Graduate Program, University of British Columbia 25 , Vancouver, Canada

32. Dept. of Paediatrics, University of Toronto 26 , Toronto, Canada

33. Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, NIH 27 , Bethesda, MD, USA

34. Dept. of Pediatrics, Division of Allergy and Immunology, Children’s Hospital of Philadelphia 28 , Philadelphia, PA, USA

35. Pediatrics, Division of Human Genetics, Children’s Hospital of Philadelphia 29 , Philadelphia, PA, USA

36. Pediatrics, Division of Pediatric Dermatology, Perelman School of Medicine, University of Pennsylvania 30 , Philadelphia, PA, USA

37. NIAID Collaborative Bioinformatics Resource, NIAID 31 , , Bethesda, MD, USA

38. NIH 31 , , Bethesda, MD, USA

39. Immunology Service, Clinical Center, NIH 32 , Bethesda, MD, USA

40. Dept. of Pediatrics, University of California San Diego 33 , La Jolla, CA, USA

41. Dept. of Medicine, Divison of Dermatology, The University of Hong Kong 34 , Hong Kong, China

42. Dept. of Paediatrics and Adolescent Medicine, Queen Mary Hospital 35 , Hong Kong, China

43. Dept. of Human Genetics, Radboud University Medical Center 36 , Nijmegen, Netherlands

44. Virtus Medical 37 , Hong Kong, China

45. Pediatric Center, Vinmec Times City International General Hospital 38 , Hanoi, Vietnam

46. Pediatrics, Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Centre of Excellence, Children’s Medical Center, University of Medical Sciences 39 , Tehran, Iran

47. Pediatrics, Allergy and Clinical Immunology, Lorestan University of Medical Sciences 40 , Khoramabad, Iran

48. Dept. of Medical Biotechnology, School of Medicine, Zanjan University of Medical Sciences 41 , Zanjan, Iran

49. School of Mathematics, Institute for Research in Fundamental Sciences 42 , Tehran, Iran

50. Dept. of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences 43 , Tehran, Iran

51. 60 , New York, NY, USA

52. St. Giles Laboratory of Human Genetics of Infectious Diseases, 60 , New York, NY, USA

53. Rockefeller Branch, 60 , New York, NY, USA

54. The Rockefeller University 60 , New York, NY, USA

55. Microbiology and Immunology, Laboratory of Clinical Bacteriology and Mycology, KU Leuven 44 , Leuven, Belgium

56. DPUO, Research Unit of Infectivology and Pediatrics Drugs Development, Bambino Gesù Children Hospital IRCCS 45 , Rome, Italy

57. Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children Hospital IRCCS 46 , Rome, Italy

58. Allergy Unit, Area of Translational Research in Pediatric Specialities, Bambino Gesù Children’s Hospital, IRCCS 47 , Rome, Italy

59. Dept. of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven 48 , Leuven, Belgium

60. Dept. of Pediatrics, Pediatric Allergy Division, University Hospitals Leuven 49 , Leuven, Belgium

61. Dept. of Pediatrics, Pediatric Pulmonology Division, AZ Sint-Jan Brugge 50 , Brugge, Belgium

62. Dept. of Pediatrics, Pediatric Pulmonology Division, University Hospitals Leuven 51 , Leuven, Belgium

63. Dept. of Pediatrics, Pediatric Gastroenterology Division, AZ Sint-Jan Brugge 52 , Brugge, Belgium

64. Genetics Program, North York General Hospital 53 , Toronto, Canada

65. Depts. of Pediatrics and Clinical Genetics, Amsterdam University Medical Centers 54 , Amsterdam, Netherlands

66. Howard Hughes Medical Institute, 55 , New York, NY, USA

67. The Rockefeller University 55 , New York, NY, USA

68. Department of Pediatrics 56 , , France

69. Necker Hospital for Sick Children, AP-HP 56 , , France

70. 57 , Tehran, Iran

71. Department of Pediatrics, 57 , Tehran, Iran

72. Children’s Medical Center, 57 , Tehran, Iran

73. Tehran University of Medical Sciences 57 , Tehran, Iran

74. Dept. of Immunology, Allergy and Rheumatology, Division of Primary Immunodeficiency, Vietnam National Children’s Hospital 58 , Hanoi, Vietnam

75. Faculty of Health Sciences, McMaster University 59 , Hamilton, Canada

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.

Funder

Canadian Institutes of Health Research

Genome British Columbia

BC Children’s Hospital Foundation

Canada Research Chair

CIHR Frederick Banting

University of British Columbia

Charles Best Canada Graduate Scholarships Doctoral Award

BC Children’s Hospital Research Institute

Vanier Canada

Elizabeth Paige Lavin Endowed Chair

National Institute of Allergy and Infectious Diseases