Heterozygous N-terminal deletion of IκBα results in functional nuclear factor κB haploinsufficiency, ectodermal dysplasia, and immune deficiency
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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- "Two aspects of the disease phenotype of patients affected by IB deficiency have long been a puzzle. The patients suffer from severe, recurrent, and potentially fatal infections despite having normal or elevated T and B cell numbers and intact in vitro T cell function (Courtois et al., 2003; Janssen et al., 2004; McDonald et al., 2007; Kawai et al., 2012). The outcome of hematopoietic stem cell transplantation (HSCT) in these patients is poor in spite of good engraftment of donor lymphoid cells. "
ABSTRACT: Patients with ectodermal dysplasia with immunodeficiency (ED-ID) caused by mutations in the inhibitor of NF-κB α (IκBα) are susceptible to severe recurrent infections, despite normal T and B cell numbers and intact in vitro lymphocyte function. Moreover, the outcome of hematopoietic stem cell transplantation (HSCT) in these patients is poor despite good engraftment. Mice heterozygous for the IκBα S32I mutation found in patients exhibited typical features of ED-ID. Strikingly, the mice lacked lymph nodes, Peyer's patches, splenic marginal zones, and follicular dendritic cells and failed to develop contact hypersensitivity (CHS) or form germinal centers (GCs), all features not previously recognized in patients and typical of defective noncanonical NF-κB signaling. Lymphotoxin β receptor (LTβR)-driven induction of chemokines and adhesion molecules mediated by both canonical and noncanonical NF-κB pathways was impaired, and levels of p100 were markedly diminished in the mutant. IκBα mutant→Rag2(-/-), but not WT→IκBα mutant, bone marrow chimeras formed proper lymphoid organs and developed CHS and GCs. Defective architectural cell function explains the immunodeficiency and poor outcome of HSCT in patients with IκBα deficiency and suggests that correction of this niche is critical for reconstituting their immune function. © 2015 Mooster et al.Journal of Experimental Medicine 01/2015; DOI:10.1084/jem.20140979 · 13.91 Impact Factor
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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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