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

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Presentation transcript:

Heterozygous N-terminal deletion of IκBα results in functional nuclear factor κB haploinsufficiency, ectodermal dysplasia, and immune deficiency Douglas R. McDonald, MD, PhD, Jana L. Mooster, Malathi Reddy, MD, Erawati Bawle, MD, Elizabeth Secord, MD, Raif S. Geha, MD Journal of Allergy and Clinical Immunology Volume 120, Issue 4, Pages 900-907 (October 2007) DOI: 10.1016/j.jaci.2007.08.035 Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Impaired TLR-induced NF-κB–dependent cytokine production by patient PBMCs. PBMCs (control, solid bars; patient, open bars) were incubated with medium, Poly I:C (TLR3), LPS (TLR4), flagellin (TLR5), 3M-13 (TLR7), or ODN2216 (TLR9). TNF-α (A) and IFN-α (B) were quantitated 12 and 48 hours after stimulation, respectively. Two independent experiments are shown. Journal of Allergy and Clinical Immunology 2007 120, 900-907DOI: (10.1016/j.jaci.2007.08.035) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Patient fibroblasts express a mutant IκBαW11X protein that does not undergo IL-1–induced phosphorylation and degradation. Western blotting of lysates from control and patient fibroblasts stimulated for the indicated times with 25 ng/mL IL-1 is shown. The blot was first probed with anti-phospho-IκBα and then stripped and reprobed sequentially with anti-IκBα, anti-N-terminal IκBα, anti-phospho-p38 MAPK, and anti-p38 MAPK as a loading control. Data shown are representative of 3 independent experiments. NL, Healthy control subject; PT, patient. Journal of Allergy and Clinical Immunology 2007 120, 900-907DOI: (10.1016/j.jaci.2007.08.035) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 NF-κB p65 is persistently bound by mutant IκBαW11X in patient fibroblasts. A, Lysates of fibroblasts stimulated with media or 25 ng/mL IL-1 for the indicated times were immunoprecipitated with nonspecific rabbit IgG (Ctrl) or anti-IκBα and were Western blotted with mouse anti-p65 and anti-IκBα antibody. Fifteen milliliters of lysate was Western blotted with anti–signal transducer and activator of transcription 1 (STAT1) Western blotting to verify equal protein content. B, Western blotting of cytosolic fractions from unstimulated and stimulated fibroblasts with anti-p65 and anti-STAT1. Data are representative of 3 independent experiments. NL, Healthy control subject; PT, patient. Journal of Allergy and Clinical Immunology 2007 120, 900-907DOI: (10.1016/j.jaci.2007.08.035) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Reduced NF-κB nuclear translocation and DNA binding in nuclear extracts from the patient's fibroblasts. A, Nuclear extracts prepared from IL-1–stimulated fibroblasts for the indicated times were Western blotted sequentially with anti-p65 (p65), anti-p50 (p50), and anti-PARP as a loading control. B, EMSA with a radiolabeled NF-κB probe. Anti-p65 antibody was used in one reaction to verify the presence of p65 in the retarded bands. Data are representative of 3 independent experiments. NL, Healthy control subject; PT, patient. Journal of Allergy and Clinical Immunology 2007 120, 900-907DOI: (10.1016/j.jaci.2007.08.035) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 IκBαW11X does not exert a dominant-negative effect. A, HEK293T cells were cotransfected with Flag-WT IκBα or Flag- IκBαW11X and 100 ng of NF-κB–luciferase reporter construct and pRL TK-Renilla reporter construct and then stimulated with media or 20 ng/mL TNF-α for 6 hours. Fold activation of luciferase activity was calculated relative to unstimulated HEK293T cells transfected with 500 ng of vector DNA. Results were normalized for transfection efficiency by using Renilla. Data are expressed as the mean ± SD of 3 experiments. B, Anti-Flag Western blot of cellular lysates. Journal of Allergy and Clinical Immunology 2007 120, 900-907DOI: (10.1016/j.jaci.2007.08.035) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions