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Case Reports
. 2008 Apr;121(4):976-82.
doi: 10.1016/j.jaci.2007.11.014. Epub 2008 Jan 7.

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

Bryn H Salt  1 , Julie E Niemela, Rahul Pandey, Eric P Hanson, Raquel P Deering, Ralph Quinones, Ashish Jain, Jordan S Orange, Erwin W Gelfand
Affiliations
Case Reports

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

Bryn H Salt et al. J Allergy Clin Immunol. 2008 Apr.

Abstract

Background: Patients with hypomorphic nuclear factor-kappaB essential modulator (NEMO) mutations have extensive phenotypic variability that can include atypical infectious susceptibility.

Objective: This study may provide important insight into immunologic mechanisms of host defense.

Methods: Immunologic evaluation, including studies of Toll-like receptor (TLR) function, was performed in a 6-month-old boy with normal ectodermal development who was diagnosed with Pneumocystis pneumonia and cytomegalovirus sepsis.

Results: Genomic and cDNA sequencing demonstrated a novel NEMO missense mutation, 337G->A, predicted to cause a D113N (aspartic acid to asparagine) substitution in the first coiled-coil region of the NEMO protein. Quantitative serum immunoglobulins, lymphocyte subset numbers, and mitogen-induced lymphocyte proliferation were essentially normal. The PBMC responses to TLR ligands were also surprisingly normal, whereas natural killer cell cytolytic activity, T-cell proliferative responses to specific antigens, and T-cell receptor-induced NF-kappaB activation were diminished.

Conclusion: Unlike the unique NEMO mutation described here, the most commonly reported mutations are clustered at the 3' end in the tenth exon, which encodes a zinc finger domain. Because specific hypomorphic variants of NEMO are associated with distinctive phenotypes, this particular NEMO mutation highlights a dispensability of the region including amino acid 113 for TLR signaling and ectodysplasin A receptor function. This region is required for certain immunoreceptor functions as demonstrated by his susceptibility to infections as well as natural killer cell and T-cell defects.

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Conflict of interest statement

Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

Figures

FIG 1
FIG 1
Map demonstrating the NEMO hypomorphism (red) in the patient relative to other related and major hypomorphisms associated with immunodeficiency. The ability of these alterations to impair TLR signaling is noted.
FIG 2
FIG 2
NK cell cytotoxicity measured by the lysis of K562 target cells at differing effector to target cell ratios using a 51Cr-release assay. Each data point was repeated in triplicate with a variation of <10%, and the experiment is representative of 2 independent experiments.
FIG 3
FIG 3
Impaired TCR-induced IκB degradation in patient T cells. Highly enriched maternal (left) and patient (right) CD3+ T cells were control-treated or activated for 30 minutes with C305 anti-TCR mAb and whole cell lysates evaluated for the presence of IκB (top) or actin (bottom) by Western blot. Numbers depict band intensity relative to control, and blots are representative of 2 experiments.
FIG 4
FIG 4
Intact TLR-induced TNF responses. Patient PBMCs (red), maternal PBMCs (blue), unrelated control donor PBMCs (green), or PBMCs from a patient with a previously described NEMO L153R hypomorphism (gold) were incubated for 18 hours with TLR ligands. Supernatants were assayed for the presence of TNF by ELISA.
FIG 5
FIG 5
Normal IκB degradation after exposure of patient cells to the TLR5 ligand flagellin. Whole-cell lysate IκBα Western blot (top) of unstimulated (left) or TLR5 ligand-stimulated (right) PBMCs. Membranes were stripped and reprobed for tubulin (bottom) as a loading control. Lysates from maternal PBMCs (left lanes) were compared with patient PBMCs (right lanes). Numbers depict band intensity relative to control, and blots are representative of 3 independent experiments.
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References

    1. Zonana J, Elder ME, Schneider LC, Orlow SJ, Moss C, Golabi M, et al. A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO) Am J Hum Genet. 2000;67:1555–1562. - PMC - PubMed
    1. Smahi A, Courtois G, Rabia SH, Doffinger R, Bodemer C, Munnich A, et al. The NF-kappaB signaling pathway in human diseases: from incontinentia pigmenti to ectodermal dysplasias and immune-deficiency syndromes. Hum Mol Genet. 2002;11:2371–2375. - PubMed
    1. Orange JS, Levy O, Geha RS. Human disease resulting from gene mutations that interfere with appropriate nuclear factor-kappaB activation. Immunol Rev. 2005;203:21–37. - PubMed
    1. Orange JS, Jain A, Ballas ZK, Schneider LC, Geha RS, Bonilla FA. The presentation and natural history of immunodeficiency caused by nuclear factor kappa B essential modulator mutation. J Allergy Clin Immunol. 2004;113:725–733. - PubMed
    1. Orange JS, Levy O, Brodeur SR, Krzewski K, Roy RM, Niemela JE, et al. Human nuclear factor kappa B essential modulator mutation can result in immunodeficiency without ectodermal dysplasia. J Allergy Clin Immunol. 2004;114:650–656. - PubMed

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