Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia

Abstract

The gene that encodes nuclear factor kappaB (NF-kappaB) essential modulator (or NEMO, also known as IKKgamma) is required for activation of the transcription factor NF-kappaB. We describe mutations in the putative zinc-finger domain of NEMO that result in an X-linked primary immunodeficiency characterized by hyper-IgM syndrome and hypohydrotic ectodermal dysplasia (XHM-ED). These mutations prevent CD40 ligand (CD40L)-mediated degradation of inhibitor of NF-kappaB alpha (IkappaB-alpha) and account for the following observations: B cells from XHM-ED patients are unable to undergo immunoglobulin class-switch recombination and antigen-presenting cells (APCs) are unable to synthesize the NF-kappaB-regulated cytokines interleukin 12 (IL-12) or tumor necrosis factor alpha (TNF-alpha) when stimulated with CD40L. Nevertheless, innate immunity is preserved in XHM-ED patients because APCs retain the capacity to respond to stimulation by lipopolysaccharide or Staphylococcus aureus Cowan's antigen (SAC). Overall, the phenotype observed in XHM-ED patients shows that the putative zinc-finger domain of NEMO has a regulatory function and demonstrates the definite requirement of CD40-mediated NF-kappaB activation for B cell immunoglobulin class-switching.

Mutations in the NF-κB signaling pathway: implications for human disease

“…Mutations generating IP (red), EDA-ID) (blue) and immunodeficiencies without EDA (green) (Smahi et al, 2000;Zonana et al, 2000;Aradhya et al, 2001a;Aradhya et al, 2001b;Do¨ffinger et al, 2001;Jain et al, 2001;Fusco et al, 2004;Orange et al, 2004;FilipeSantos et al, 2006;Puel et al, 2006) (Zonana et al, 2000;Do¨ffinger et al, 2001;Jain et al, 2001;Aradhya et al, 2001a In contrast, the association of NEMO mutations with the EDA-ID defect in skin adnexes development is more puzzling. Because morphogenesis of all the affected appendages, such as hair, sweat glands and teeth, is dependent upon a specific interaction between the TNF-like ligand ectodysplasin A and its receptor EDAR (Mikkola and Thesleff, 2003), the analysis of EDA-ID pathology has revealed an unexpected link between ectodysplasin signaling and NF-kB activation, involving NEMO.…”

IKBKG (nuclear factor-κB essential modulator) mutation can be associated with opportunistic infection without impairing Toll-like receptor function

“…Nuclear factor-κB essential modulator sequencing was performed by using a series of primer sets directed at amplifying each of the individual NEMO exons as described 8 (primers available on request). To confirm that the identified NEMO mutation was in the functional NEMO gene and not the NEMO pseudogene, cDNA was prepared, and the sequence corresponding to the expressed NEMO message was amplified and sequenced as described.…”

“…To confirm that the identified NEMO mutation was in the functional NEMO gene and not the NEMO pseudogene, cDNA was prepared, and the sequence corresponding to the expressed NEMO message was amplified and sequenced as described. 8 …”

NF-κB-related genetic diseases

“…Most of them indeed carry mutations in NEMO but instead of leading to large truncations of the NEMO molecule as observed in IP, the mutations are mostly missense mutations or small deletions only affecting the ZF (Table 1). [30][31][32][33][34] Their molecular characterization is likely to provide valuable insights into NEMO function but for only few of them some specific defect has been identified.…”