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, Alessandra Simonetti, Paolo Rossi, Gigliola Di Matteo, Maria Luisa Romiti, Silvia Di Cesare, Luigi Notarangelo, Raif S. Geha, Douglas R. McDonald

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
JournalJournal of Allergy and Clinical Immunology
Volume126
Issue number1
DOIs
Publication statusPublished - Jul 2010

Keywords

  • 5′ untranslated region mutation
  • immune deficiency
  • NEMO
  • recurrent infections

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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