Autosomal recessive IRAK-4 deficiency leads to impaired TLR responses in leukocytes and is associated with increased susceptibility to pyogenic bacterial infections in childhood (Picard C et al. 2003; Medvedev AE et al. 2003; Yamamoto T et al. 2014). Unlike most of the identified gene variants of IRAK4 with nonsense or frame shift mutations that create premature stop codons and result in abolished IRAK4 production, the protein level of missence variant IRAK4 R12C was comparable with wild type (WT) when expressed in human embryonic kidney 293 (HEK293T) cells (Ku CL et al. 2007; Yamamoto T et al. 2014). Analytical gel filtration of recombinant WT or mutant IRAK4 and MyD88 proteins revealed that IRAK4 R12C failed to form a complex with MyD88. These results are in agreement with nuclear magnetic resonance (NMR) titration study that showed a lower affinity of IRAK R12C variant towards 1H-15N-labeled MyD88 N-terminal domain (Yamamoto T et al. 2014).
Hoarau, C, Gérard, B, Lescanne, E, Henry, D, François, S, Lacapère, JJ, El Benna, J, Dang, PM, Grandchamp, B, Lebranchu, Y, Gougerot-Pocidalo, MA, Elbim, C
Yamamoto, T, Tsutsumi, N, Tochio, H, Ohnishi, H, Kubota, K, Kato, Z, Shirakawa, M, Kondo, N
Loss of function of IRAK4 R12C [cytosol]
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