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Human Germline Heterozygous Gain-Of-Function Stat6 Variants Cause Severe Allergic Disease Publisher



Sharma M1 ; Leung D2 ; Momenilandi M3, 4 ; Jones LCW1 ; Pacillo L5, 6, 7 ; James AE8 ; Murrell JR9 ; Delafontaine S10, 11 ; Maimaris J12, 13 ; Vaseghishanjani M1 ; Del Bel KL1 ; Lu HY14, 15, 16 ; Chua GT2, 17 ; Di Cesare S5, 7 Show All Authors
Authors
  1. Sharma M1
  2. Leung D2
  3. Momenilandi M3, 4
  4. Jones LCW1
  5. Pacillo L5, 6, 7
  6. James AE8
  7. Murrell JR9
  8. Delafontaine S10, 11
  9. Maimaris J12, 13
  10. Vaseghishanjani M1
  11. Del Bel KL1
  12. Lu HY14, 15, 16
  13. Chua GT2, 17
  14. Di Cesare S5, 7
  15. Fornes O18, 19
  16. Liu Z2
  17. Di Matteo G6, 7
  18. Fu MP20, 21
  19. Amodio D6
  20. Tam IYS2
  21. Chan GSW22
  22. Sharma AA23
  23. Dalmann J1
  24. Van Der Lee R18, 19
  25. Blanchardrohner G1, 24
  26. Lin S1
  27. Philippot Q3, 4
  28. Richmond PA1, 18
  29. Lee JJ18, 25
  30. Matthews A18, 26
  31. Seear M1
  32. Turvey AK1
  33. Philips RL27
  34. Brownwhitehorn TF28
  35. Gray CJ29
  36. Izumi K29
  37. Treat JR30
  38. Wood KH9
  39. Lack J31
  40. Khleborodova A31
  41. Niemela JE32
  42. Yang X2
  43. Liang R2
  44. Kui L2, 33
  45. Wong CSM34
  46. Poon GWK35
  47. Hoischen A36
  48. Van Der Made CI36
  49. Yang J2
  50. Chan KW2
  51. Da Rosa Duque JS2
  52. Lee PPW2
  53. Ho MHK2, 37
  54. Chung BHY2
  55. Le HTM38
  56. Yang W2
  57. Rohani P39
  58. Fouladvand A40
  59. Roknizadeh H41
  60. Changiashtiani M42
  61. Miryounesi M43
  62. Puel A3, 4, 60
  63. Shahrooei M44
  64. Finocchi A5, 7
  65. Rossi P5, 45
  66. Rivalta B5, 6, 7
  67. Cifaldi C7
  68. Novelli A46
  69. Passarelli C46
  70. Arasi S47
  71. Bullens D48, 49
  72. Sauer K50, 51
  73. Claeys T52
  74. Biggs CM1
  75. Morris EC12, 13
  76. Rosenzweig SD32
  77. Oshea JJ27
  78. Wasserman WW18
  79. Bedford HM26, 53
  80. Van Karnebeek CDM18, 54
  81. Palma P5, 6
  82. Burns SO12, 13
  83. Meyts I10, 11
  84. Casanova JL3, 4, 55, 56, 60
  85. Lyons JJ8
  86. Parvaneh N57
  87. Van Nguyen AT58
  88. Cancrini C5, 7
  89. Heimall J28
  90. Ahmed H59
  91. Mckinnon ML19
  92. Lau YL2
  93. Beziat V3, 4, 60
  94. Turvey SE1
Show Affiliations
Authors Affiliations
  1. 1. Dept. of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, Canada
  2. 2. Dept. of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong
  3. 3. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker Hospital for Sick Children, Paris, France
  4. 4. Imagine Institute, University of Paris-Cite, Paris, France
  5. 5. Dept. of System Medicine, Pediatric Chair, University of Tor Vergata, Rome, Italy
  6. 6. Academic Dept. of Pediatrics (DPUO), Unit of Clinical Immunology and Vaccinology, IRCCS Bambin Gesu Children Hospital, Rome, Italy
  7. 7. Research Unit of Primary Immunodeficiency, IRCCS Bambin Gesu Children Hospital, Rome, Italy
  8. 8. Translational Allergic Immunopathology Unit, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States
  9. 9. Pathology and Laboratory Medicine, Division of Genomic Diagnostics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
  10. 10. Dept. of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, KU Leuven, Leuven, Belgium
  11. 11. Dept. of Pediatrics, Pediatric Immunodeficiencies Division, University Hospitals Leuven, Leuven, Belgium
  12. 12. Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London, United Kingdom
  13. 13. Dept. of Immunology, Royal Free London NHS Foundation Trust, London, United Kingdom
  14. 14. Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
  15. 15. Dept. of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States
  16. 16. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, United States
  17. 17. Allergy Centre, Union Hospital, Hong Kong
  18. 18. Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute, Vancouver, Canada
  19. 19. Dept. of Medical Genetics, University of British Columbia, Vancouver, Canada
  20. 20. Dept. of Medical Genetics, The University of British Columbia, Vancouver, Canada
  21. 21. Genome Science and Technology Program, Faculty of Science, The University of British Columbia, Vancouver, Canada
  22. 22. Dept. of Pathology, Queen Mary Hospital, Hong Kong
  23. 23. Dept. of Pathology, Emory University, Atlanta, GA, United States
  24. 24. 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, Geneva, Switzerland
  25. 25. Genome Science and Technology Graduate Program, University of British Columbia, Vancouver, Canada
  26. 26. Dept. of Paediatrics, University of Toronto, Toronto, Canada
  27. 27. Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, United States
  28. 28. Dept. of Pediatrics, Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
  29. 29. Pediatrics, Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
  30. 30. Pediatrics, Division of Pediatric Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
  31. 31. NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, MD, United States
  32. 32. Immunology Service, Clinical Center, NIH, Bethesda, MD, United States
  33. 33. Dept. of Pediatrics, University of California San Diego, La Jolla, CA, United States
  34. 34. Dept. of Medicine, Divison of Dermatology, The University of Hong Kong, Hong Kong
  35. 35. Dept. of Paediatrics and Adolescent Medicine, Queen Mary Hospital, Hong Kong
  36. 36. Dept. of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
  37. 37. Virtus Medical, Hong Kong
  38. 38. Pediatric Center, Vinmec Times City International General Hospital, Hanoi, Viet Nam
  39. 39. Pediatrics, Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Centre of Excellence, Children’s Medical Center, University of Medical Sciences, Tehran, Iran
  40. 40. Pediatrics, Allergy and Clinical Immunology, Lorestan University of Medical Sciences, Khoramabad, Iran
  41. 41. Dept. of Medical Biotechnology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
  42. 42. School of Mathematics, Institute for Research in Fundamental Sciences, Tehran, Iran
  43. 43. Dept. of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  44. 44. Microbiology and Immunology, Laboratory of Clinical Bacteriology and Mycology, KU Leuven, Leuven, Belgium
  45. 45. DPUO, Research Unit of Infectivology and Pediatrics Drugs Development, Bambino Gesu Children Hospital IRCCS, Rome, Italy
  46. 46. Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesu Children Hospital IRCCS, Rome, Italy
  47. 47. Allergy Unit, Area of Translational Research in Pediatric Specialities, Bambino Gesu Children’s Hospital, IRCCS, Rome, Italy
  48. 48. Dept. of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium
  49. 49. Dept. of Pediatrics, Pediatric Allergy Division, University Hospitals Leuven, Leuven, Belgium
  50. 50. Dept. of Pediatrics, Pediatric Pulmonology Division, AZ Sint-Jan Brugge, Brugge, Belgium
  51. 51. Dept. of Pediatrics, Pediatric Pulmonology Division, University Hospitals Leuven, Leuven, Belgium
  52. 52. Dept. of Pediatrics, Pediatric Gastroenterology Division, AZ Sint-Jan Brugge, Brugge, Belgium
  53. 53. Genetics Program, North York General Hospital, Toronto, Canada
  54. 54. Depts. of Pediatrics and Clinical Genetics, Amsterdam University Medical Centers, Amsterdam, Netherlands
  55. 55. Howard Hughes Medical Institute, The Rockefeller University, New York, NY, United States
  56. 56. Department of Pediatrics, Necker Hospital for Sick Children, AP-HP, France
  57. 57. Department of Pediatrics, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
  58. 58. Dept. of Immunology, Allergy and Rheumatology, Division of Primary Immunodeficiency, Vietnam National Children’s Hospital, Hanoi, Viet Nam
  59. 59. Faculty of Health Sciences, McMaster University, Hamilton, Canada
  60. 60. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, United States

Source: Journal of Experimental Medicine Published:2023


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. © 2023 Sharma et al.
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