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Sars-Cov-2 Brainstem Encephalitis in Human Inherited Dbr1 Deficiency Publisher



Chan YH1 ; Lundberg V2, 3 ; Le Pen J4 ; Yuan J5 ; Lee D1, 6, 7 ; Pinci F8 ; Volpi S9, 10 ; Nakajima K1 ; Bondet V11 ; Akesson S3 ; Khobrekar NV5 ; Bodansky A12 ; Du L13 ; Melander T14 Show All Authors
Authors
  1. Chan YH1
  2. Lundberg V2, 3
  3. Le Pen J4
  4. Yuan J5
  5. Lee D1, 6, 7
  6. Pinci F8
  7. Volpi S9, 10
  8. Nakajima K1
  9. Bondet V11
  10. Akesson S3
  11. Khobrekar NV5
  12. Bodansky A12
  13. Du L13
  14. Melander T14
  15. Mariaggi AA15
  16. Seeleuthner Y6, 7
  17. Saleh TS16
  18. Chakravarty D17, 18
  19. Marits P19, 20
  20. Dobbs K21
  21. Vonlanthen S19, 20
  22. Hennings V2, 3
  23. Thorn K3
  24. Rinchai D1
  25. Bizien L6, 7
  26. Chaldebas M1
  27. Sobh A22
  28. Ozcelik T23
  29. Keles S24
  30. Alkhater SA25, 26
  31. Prando C27
  32. Meyts I28
  33. Wilson MR17, 18
  34. Rosain J1, 6, 7
  35. Jouanguy E1, 6, 7
  36. Aubart M6, 7, 29
  37. Abel L1, 6, 7
  38. Mogensen TH30
  39. Panhammarstrom Q13
  40. Gao D31, 32
  41. Duffy D11
  42. Cobat A6, 7
  43. Berg S2
  44. Notarangelo LD21
  45. Harschnitz O8
  46. Rice CM4
  47. Studer L5
  48. Casanova JL1, 6, 7, 33, 98, 99
  49. Ekwall O2, 3
  50. Zhang SY1, 6, 7, 96
  51. Bastard P35
  52. Borghesi A36, 37
  53. Bousfiha A38
  54. Boyarchuk O39
  55. Brodin P40
  56. Bustamante J35
  57. Casari G41
  58. Chevalier R35
  59. Christodoulou J42
  60. Colobran R45
  61. Condinoneto A46
  62. Aldave Becerra JC47
  63. Arkin L48
  64. Andreakos E49
  65. Thorball CW50
  66. Espinosa S51
  67. Flores C52, 53, 54
  68. Geraldo A35
  69. Halwani R55
  70. Hatipoglu N56
  71. Melaiki B57
  72. Fellay J58, 59, 60
  73. Gagro A61, 100
  74. Itan Y62
  75. Jeewandara C63
  76. Haerynck F64
  77. Mansouri D65, 66, 67
  78. Naesens L64
  79. Ng LFP68
  80. Okamoto K69
  81. Soler Palacin P70
  82. Renia L71, 72, 73
  83. Onofre AP74
  84. Resnick IB77, 78
  85. Ranco Restrepo JLF79
  86. Riviere JG70
  87. Scherbina A80
  88. Sediva A81
  89. Seppanen MRJ82
  90. Su H83
  91. Tangye SG84, 101
  92. Temel SG85, 86
  93. Tayoun AA87, 88
  94. Turvey S89, 90
  95. Furkan Uddin KM91, 92
  96. Van De Beek D93
  97. Le Voyer T35
  98. Vinh DC94, 95

Source: Journal of Experimental Medicine Published:2024


Abstract

Inherited deficiency of the RNA lariat–debranching enzyme 1 (DBR1) is a rare etiology of brainstem viral encephalitis. The cellular basis of disease and the range of viral predisposition are unclear.We report inherited DBR1 deficiency in a 14-year-old boywho suffered from isolated SARS-CoV-2 brainstem encephalitis. The patient is homozygous for a previously reported hypomorphic and pathogenic DBR1 variant (I120T). Consistently, DBR1 I120T/I120T fibroblasts from affected individuals from this and another unrelated kindred have similarly low levels of DBR1 protein and high levels of RNA lariats. DBR1 I120T/I120T human pluripotent stem cell (hPSC)–derived hindbrain neurons are highly susceptible to SARS-CoV-2 infection. Exogenous WT DBR1 expression in DBR1 I120T/I120T fibroblasts and hindbrain neurons rescued the RNA lariat accumulation phenotype. Moreover, expression of exogenous RNA lariats, mimicking DBR1 deficiency, increased the susceptibility ofWT hindbrain neurons to SARS-CoV-2 infection. Inborn errors of DBR1 impair hindbrain neuron–intrinsic antiviral immunity, predisposing to viral infections of the brainstem, including that by SARS-CoV-2. © 2024 Chan et al.
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