Immune deficiency caused by impaired expression of nuclear factor-kappaB essential modifier (NEMO) because of a mutation in the 5' untranslated region of the NEMO gene

J Allergy Clin Immunol. 2010 Jul;126(1):127-32.e7. doi: 10.1016/j.jaci.2010.04.026. Epub 2010 Jun 12.

Abstract

Background: Nuclear factor-kappaB (NF-kappaB) is a key transcription factor that regulates both innate and adaptive immunity as well as ectodermal development. Mutations in the coding region of the IkappaB kinase gamma/NF-kappaB 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-alpha and IFN-alpha 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-kappaB activation was assessed by nuclear translocation of p65 and luciferase reporter gene assays.

Results: TLR-induced TNF-alpha and IFN-alpha 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-kappaB p65 nuclear translocation in the patient's EBV B cells after TLR7 ligation was defective. NF-kappaB-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.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural

MeSH terms

  • 5' Untranslated Regions / genetics*
  • Child
  • Cytokines / biosynthesis
  • Humans
  • I-kappa B Kinase / analysis
  • I-kappa B Kinase / genetics*
  • I-kappa B Proteins / metabolism
  • Immunologic Deficiency Syndromes / etiology*
  • Immunologic Deficiency Syndromes / genetics
  • Interleukin-1beta / pharmacology
  • Male
  • Mutation*
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism
  • Phosphorylation
  • RNA Splice Sites
  • RNA, Messenger / analysis
  • Toll-Like Receptors / physiology

Substances

  • 5' Untranslated Regions
  • Cytokines
  • I-kappa B Proteins
  • IKBKG protein, human
  • Interleukin-1beta
  • NF-kappa B
  • NFKBIA protein, human
  • RNA Splice Sites
  • RNA, Messenger
  • Toll-Like Receptors
  • NF-KappaB Inhibitor alpha
  • I-kappa B Kinase