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IRAK-4 mutation (Q293X): rapid detection and characterization of defective post-transcriptional TLR/IL-1R responses in human myeloid and non-myeloid cells

Journal article
Authors D. J. Davidson
A. J. Currie
D. M. Bowdish
K. L. Brown
C. M. Rosenberger
R. C. Ma
Johan Bylund
P. A. Campsall
A. Puel
C. Picard
J. L. Casanova
S. E. Turvey
R. E. Hancock
R. S. Devon
D. P. Speert
Published in J Immunol
Volume 177
Issue 11
Pages 8202-11
Publication year 2006
Published at Institute of Medicine, Department of Rheumatology and Inflammation Research
Pages 8202-11
Language en
Keywords Amino Acid Sequence, Blotting, Western, Cytokines/biosynthesis, Extracellular Signal-Regulated MAP Kinases/immunology, Fibroblasts/*immunology, Gene Expression, Humans, Immune System Diseases/*genetics, Interleukin-1 Receptor-Associated Kinases/*genetics, Male, Molecular Sequence Data, Mutation, Myeloid Cells/*immunology, Myeloid Differentiation Factor 88/immunology, NF-kappa B/immunology, Pedigree, RNA, Messenger/analysis, Receptors, Interleukin-1/*immunology, Reverse Transcriptase Polymerase Chain Reaction, Toll-Like Receptors/*immunology, Transcription, Genetic
Subject categories Medical and Health Sciences


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-1beta, and TNF-alpha signaling. We demonstrate transcriptional and post-transcriptional defects despite NF-kappaB 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.

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