Heterozygous N-terminal deletion of IκBα results in functional nuclear factor κB haploinsufficiency, ectodermal dysplasia, and immune deficiency

Harvard University, Cambridge, Massachusetts, United States
Journal of Allergy and Clinical Immunology (Impact Factor: 11.25). 11/2007; 120(4):900-7. DOI: 10.1016/j.jaci.2007.08.035
Source: PubMed

ABSTRACT Nuclear factor kappaB (NF-kappaB) is a master transcriptional regulator critical for ectodermal development and normal innate and adaptive immune function. Mutations in the IkappaB kinase gamma/NF-kappaB essential modifier have been described in male subjects with the syndrome of X-linked ectodermal dysplasia with immune deficiency that results from impaired activation of NF-kappaB.
We sought to determine the genetic cause of ectodermal dysplasia with immune deficiency in a female patient.
Toll-like receptor-induced production of the NF-kappaB-dependent cytokines TNF-alpha and IFN-alpha was examined by means of ELISA, the patient's IkappaBalpha gene was sequenced, and NF-kappaB activation was evaluated by means of electrophoretic mobility shift assay and NF-kappaB-luciferase assays in transfectants.
Toll-like receptor function was impaired in the patient. Sequencing of the patient's IkappaBalpha gene revealed a novel heterozygous mutation at amino acid 11 (W11X). The mutant IkappaBalphaW11X protein did not undergo ligand-induced phosphorylation or degradation and retained NF-kappaB in the cytoplasm. This led to roughly a 50% decrease in NF-kappaB DNA-binding activity, leading to functional haploinsufficiency of NF-kappaB activation. Unlike the only other reported IkappaBalpha mutant associated with ectodermal dysplasia associated with immune deficiency (ED-ID), S32I, IkappaBalphaW11X exerted no dominant-negative effect.
Functional NF-kappaB haploinsufficiency was associated with ED-ID, and this strongly suggests that normal ectodermal development and immune function are stringently dependent on NF-kappaB in that they might require more than half of normal NF-kappaB activity.
Although ED-ID is well described in male subjects, female subjects can present with a similar syndrome of ectodermal dysplasia with immune deficiency resulting from mutations in autosomal genes within the NF-kappaB pathway.

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    • "In other genes, N-terminally truncated protein fragments directed by reinitiating mRNAs with 59 nonsense mutations can assume significant residual function, thus showing a milder clinical phenotype than mutations more 39 or null mutations. These include the genes for RAG1 (Santagata et al. 2000), NBS1 (Maser et al. 2001), DAX1 (Ozisik et al. 2003), ATRX (Howard et al. 2004), FOXL2 (Moumne et al. 2005), BRCA1 (Buisson et al. 2006), ATP7A (Paulsen et al. 2006), RB1 (Sanchez-Sanchez et al. 2007), NEMO (Puel et al. 2006), IkBa (McDonald et al. 2007), PHOX2B (Trochet et al. 2009), DMD (Gurvich et al. 2009), and FAC (Yamashita et al. 1996). A notable exception is the expression of a DN25 isoform of TP63 expressed from an allele with a nonsense mutation at codon 11 that manifests dominant effects and is associated with a Rapp-Hodkin/ Hay-Wells like syndrome (Rinne et al. 2008). "
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