TY - JOUR
T1 - 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
AU - Mooster, Jana L.
AU - Cancrini, Caterina
AU - Simonetti, Alessandra
AU - Rossi, Paolo
AU - Di Matteo, Gigliola
AU - Romiti, Maria Luisa
AU - Di Cesare, Silvia
AU - Notarangelo, Luigi
AU - Geha, Raif S.
AU - McDonald, Douglas R.
PY - 2010/7
Y1 - 2010/7
N2 - Background: Nuclear factor-κB (NF-κB) is a key transcription factor that regulates both innate and adaptive immunity as well as ectodermal development. Mutations in the coding region of the IκB kinase γ/NF-κB essential modifier (NEMO) gene cause X-linked ectodermal dysplasia with immunodeficiency. Objective: To determine the genetic cause of recurrent sinopulmonary infections and dysgammaglobulinemia in a patient with a normal NEMO coding sequence and his affected brother. Methods: TNF-α and IFN-α production in response to Toll-like receptor (TLR) stimulation was analyzed by ELISA, NEMO mRNA levels were measured by quantitative PCR, and NEMO protein expression was measured by Western blotting. NF-κB activation was assessed by nuclear translocation of p65 and luciferase reporter gene assays. Results: TLR-induced TNF-α and IFN-α production by PBMCs was impaired in the patient and his brother. Sequencing of the patient's NEMO gene revealed a novel mutation in the 5′ untranslated region, which was also present in the brother, resulting in abnormally spliced transcripts and a 4-fold reduction in mRNA levels. NEMO protein levels in EBV transformed B cells and fibroblasts from the index patient were 8-fold lower than normal controls. NF-κB p65 nuclear translocation in the patient's EBV B cells after TLR7 ligation was defective. NF-κB-dependent luciferase gene expression in IL-1-stimulated fibroblasts from the patient was impaired. Conclusion: This is the first description of immune deficiency resulting from low expression of a normal NEMO protein.
AB - Background: Nuclear factor-κB (NF-κB) is a key transcription factor that regulates both innate and adaptive immunity as well as ectodermal development. Mutations in the coding region of the IκB kinase γ/NF-κB essential modifier (NEMO) gene cause X-linked ectodermal dysplasia with immunodeficiency. Objective: To determine the genetic cause of recurrent sinopulmonary infections and dysgammaglobulinemia in a patient with a normal NEMO coding sequence and his affected brother. Methods: TNF-α and IFN-α production in response to Toll-like receptor (TLR) stimulation was analyzed by ELISA, NEMO mRNA levels were measured by quantitative PCR, and NEMO protein expression was measured by Western blotting. NF-κB activation was assessed by nuclear translocation of p65 and luciferase reporter gene assays. Results: TLR-induced TNF-α and IFN-α production by PBMCs was impaired in the patient and his brother. Sequencing of the patient's NEMO gene revealed a novel mutation in the 5′ untranslated region, which was also present in the brother, resulting in abnormally spliced transcripts and a 4-fold reduction in mRNA levels. NEMO protein levels in EBV transformed B cells and fibroblasts from the index patient were 8-fold lower than normal controls. NF-κB p65 nuclear translocation in the patient's EBV B cells after TLR7 ligation was defective. NF-κB-dependent luciferase gene expression in IL-1-stimulated fibroblasts from the patient was impaired. Conclusion: This is the first description of immune deficiency resulting from low expression of a normal NEMO protein.
KW - 5′ untranslated region mutation
KW - immune deficiency
KW - NEMO
KW - recurrent infections
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U2 - 10.1016/j.jaci.2010.04.026
DO - 10.1016/j.jaci.2010.04.026
M3 - Article
C2 - 20542322
AN - SCOPUS:77953961001
VL - 126
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
SN - 0091-6749
IS - 1
ER -