IRAK-4 Mutation (Q293X): Rapid Detection and Characterization of Defective Post-Transcriptional TLR/IL-1R Responses in Human Myeloid and Non-Myeloid Cells Journal Articles uri icon

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  • Abstract Innate immunodeficiency has recently been reported as resulting from the Q293X IRAK-4 mutation with consequent defective TLR/IL-1R signaling. In this study we report a method for the rapid allele-specific detection of this mutation and demonstrate both cell type specificity and ligand specificity in defective IL-1R-associated kinase (IRAK)-4-deficient cellular responses, indicating differential roles for this protein in human PBMCs and primary dermal fibroblasts and in LPS, IL-1β, and TNF-α signaling. We demonstrate transcriptional and post-transcriptional defects despite NF-κB signaling and intact MyD88-independent signaling and propose that dysfunctional complex 1 (IRAK1/TRAF6/TAK1) signaling, as a consequence of IRAK-4 deficiency, generates specific defects in MAPK activation that could underpin this patient’s innate immunodeficiency. These studies demonstrate the importance of studying primary human cells bearing a clinically relevant mutation; they underscore the complexity of innate immune signaling and illuminate novel roles for IRAK-4 and the fundamental importance of accessory proinflammatory signaling to normal human innate immune responses and immunodeficiencies.


  • Davidson, Donald J
  • Currie, Andrew J
  • Bowdish, Dawn
  • Brown, Kelly L
  • Rosenberger, Carrie M
  • Ma, Rebecca C
  • Bylund, Johan
  • Campsall, Paul A
  • Puel, Anne
  • Picard, Capucine
  • Casanova, Jean-Laurent
  • Turvey, Stuart E
  • Hancock, Robert EW
  • Devon, Rebecca S
  • Speert, David P

publication date

  • December 1, 2006

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