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Immune deficiency caused by impaired expression of nuclear factor-κB essential modifier (NEMO) because of a mutation in the 5′ untranslated region of.

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Presentation on theme: "Immune deficiency caused by impaired expression of nuclear factor-κB essential modifier (NEMO) because of a mutation in the 5′ untranslated region of."— Presentation transcript:

1 Immune deficiency caused by impaired expression of nuclear factor-κB essential modifier (NEMO) because of a mutation in the 5′ untranslated region of the NEMO gene  Jana L. Mooster, Caterina Cancrini, MD, PhD, Alessandra Simonetti, MD, Paolo Rossi, MD, PhD, Gigliola Di Matteo, PhD, Maria Luisa Romiti, PhD, Silvia Di Cesare, Luigi Notarangelo, MD, Raif S. Geha, MD, Douglas R. McDonald, MD, PhD  Journal of Allergy and Clinical Immunology  Volume 126, Issue 1, Pages e7 (July 2010) DOI: /j.jaci Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Impaired TLR-induced NF-κB–dependent cytokine production by patient PBMCs. PBMCs were incubated with medium or TLR ligands for 24 hours, and TNF-α (A) and IFN-α (B) were quantified. Graphs show the mean and SD of 4 independent experiments using PBMCs from the index patient and healthy controls (n = 4). ∗P < .05; ∗∗∗P < C, TNF-α production in PBMCs from the patient's affected brother. PMA, Phorbol 12-myristate 13-acetate. Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 Decreased NEMO protein and mRNA levels in the patient. Western blots from PBMC lysates from control, index patient, affected brother, and unaffected mother (A) and EBV B-cell lysates (B). C, Scanning densitometry of NEMO protein levels for each EBV B cell line, normalized to actin. Controls arbitrarily set to 1. D, qPCR analysis of NEMO mRNA levels, normalized to GAPDH, in EBV B-cell lines from index patient, brother, and 8 controls. Bar represents the mean. Dashed lines span the 95% CI. Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 The patients' NEMO mutation results in 2 aberrant mRNA products. A, Representation of normal NEMO splicing. ∗Patient's mutation. mRNA splicing using exon 1A, 1B, or 1C is depicted; arrows represent PCR primers used. B, Agarose gel showing control and patient NEMO RT-PCR products containing exons 1A, 1C, and 1B. C, Schematic of aberrant NEMO exon 1B transcripts in the patient. Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 NF-κB signaling is reduced in the patient. A, Western blot of lysates from fibroblasts stimulated with IL-1β. B, Western blot of p65 nuclear translocation in TLR7-stimulated EBV B cells. C, NF-κB–luciferase reporter assay in fibroblasts treated 6 hours with IL-1β. Fold activation represents mean and SD of 8 experiments using patient fibroblasts and 3 healthy controls. Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Normal ectodermal development in the index patient at 11 years of age
Normal ectodermal development in the index patient at 11 years of age. Notice normal dentition and hairline. Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Western blot showing expression of NEMO cDNA isoforms amplified from normal and patient cells. NEMO cDNA using exons 1B and 1C were amplified from cDNA isolated from normal fibroblasts, and the misspliced 1B isoforms were amplified from cDNA isolated from patient fibroblasts. The PCR products were cloned into the pCMV-Tag4a vector and expressed in T293 HEK cells (top) or in NEMO–/– mouse embryonic fibroblasts (bottom). Note the presence of the endogenous NEMO band in T293 cells but not in NEMO-deficient murine embryonic fibroblasts (MEFs). Journal of Allergy and Clinical Immunology  , e7DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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