Defective IRAK4 variants do not bind MyD88:MAL:BTK:activated TLR2/4

Stable Identifier
Reaction [transition]
Homo sapiens
Related Species
Chlamydia trachomatis, Neisseria meningitidis serogroup B
IRAK4 deficiency blocks formation of the MyD88-IRAK4 Myddosome in TLR2/4 pathway
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Patients with an autosomal recessive form of IRAK4 deficiency bear homozygous or compound heterozygous mutations in the IRAK4 gene, that result in increased susceptibility to pyogenic bacterial infections in early childhood (Picard C et al. 2010; Picard C et al. 2011). Most of the mutations are nonsense or frame shift, that create premature stop codons leading to abolished IRAK4 production (Picard C et al. 2003; Ku CL et al. 2007; Yamamoto T et al. 2014). Here we describe two nonsense mutations that have been shown to compromise TLR2 and TLR4 signaling in response to their agonists Pam3CSK4 (TLR1/2), Pam2CSK4 (TLR2/6) and LPS (TLR4) (Ku CL et al. 2007).
Literature References
PubMed ID Title Journal Year
17893200 Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity

Abel, L, Li, X, Sanlaville, D, von Bernuth, H, Miller, R, Al-Hajjar, S, Day-Good, NK, Roifman, C, Tang, M, Hara, T, Barrat, FJ, Levy, O, Holland, SM, Ehl, S, Smart, J, Gallin, J, Bossuyt, X, Geissmann, F, Speert, D, McDonald, D, Ku, CL, Takada, H, Chrabieh, M, Rodriguez-Gallego, C, Issekutz, AC, Yang, K, Garty, BZ, Puel, A, Cunningham, CK, Al-Ghonaium, A, Chang, HH, Picard, C, MarĂ³di, L, Zhang, SY, Vivier, E, Chapel, H, Casanova, JL

J. Exp. Med. 2007
24316379 Functional assessment of the mutational effects of human IRAK4 and MyD88 genes

Kondo, N, Shirakawa, M, Ohnishi, H, Tochio, H, Kato, Z, Tsutsumi, N, Kubota, K, Yamamoto, T

Mol. Immunol. 2014
12637671 Pyogenic bacterial infections in humans with IRAK-4 deficiency

Ozinsky, A, Dupuis, S, Tufenkeji, H, Al-Rayes, H, Al-Hajjar, S, Lammas, D, Frayha, HH, Day, NK, Hitchcock, R, Bustamante, J, Gougerot-Pocidalo, MA, Elbim, C, Feinberg, J, Aderem, A, Hawn, TR, Al-Mohsen, IZ, Al-Jumaah, S, Ku, CL, Yang, K, Bonnet, M, Puel, A, Al-Ghonaium, A, Picard, C, Davies, G, Haraguchi, S, Rucker, R, Good, RA, Soudais, C, Casanova, JL, Fieschi, C

Science 2003
Normal reaction
Functional status

Loss of function of IRAK4 variants [cytosol]

Name Identifier Synonyms
primary immunodeficiency disease DOID:612 immune deficiency disorder, immunodeficiency syndrome, hypoimmunity
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