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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

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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