Heterozygous N-terminal deletion of IkappaBalpha results in functional nuclear factor kappaB haploinsufficiency, ectodermal dysplasia, and immune deficiency

J Allergy Clin Immunol. 2007 Oct;120(4):900-7. doi: 10.1016/j.jaci.2007.08.035.


Background: Nuclear factor kappaB (NF-kappaB) is a master transcriptional regulator critical for ectodermal development and normal innate and adaptive immune function. Mutations in the IkappaB kinase gamma/NF-kappaB essential modifier have been described in male subjects with the syndrome of X-linked ectodermal dysplasia with immune deficiency that results from impaired activation of NF-kappaB.

Objectives: We sought to determine the genetic cause of ectodermal dysplasia with immune deficiency in a female patient.

Methods: Toll-like receptor-induced production of the NF-kappaB-dependent cytokines TNF-alpha and IFN-alpha was examined by means of ELISA, the patient's IkappaBalpha gene was sequenced, and NF-kappaB activation was evaluated by means of electrophoretic mobility shift assay and NF-kappaB-luciferase assays in transfectants.

Results: Toll-like receptor function was impaired in the patient. Sequencing of the patient's IkappaBalpha gene revealed a novel heterozygous mutation at amino acid 11 (W11X). The mutant IkappaBalphaW11X protein did not undergo ligand-induced phosphorylation or degradation and retained NF-kappaB in the cytoplasm. This led to roughly a 50% decrease in NF-kappaB DNA-binding activity, leading to functional haploinsufficiency of NF-kappaB activation. Unlike the only other reported IkappaBalpha mutant associated with ectodermal dysplasia associated with immune deficiency (ED-ID), S32I, IkappaBalphaW11X exerted no dominant-negative effect.

Conclusions: Functional NF-kappaB haploinsufficiency was associated with ED-ID, and this strongly suggests that normal ectodermal development and immune function are stringently dependent on NF-kappaB in that they might require more than half of normal NF-kappaB activity.

Clinical implications: Although ED-ID is well described in male subjects, female subjects can present with a similar syndrome of ectodermal dysplasia with immune deficiency resulting from mutations in autosomal genes within the NF-kappaB pathway.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Child
  • Codon, Nonsense*
  • Cytokines / biosynthesis
  • Ectodermal Dysplasia / genetics*
  • Female
  • Gene Deletion
  • Humans
  • I-kappa B Proteins / genetics*
  • I-kappa B Proteins / metabolism
  • Immunologic Deficiency Syndromes / genetics*
  • Interleukin-1 / pharmacology
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / physiology*
  • Phosphorylation
  • Toll-Like Receptors / physiology


  • Codon, Nonsense
  • Cytokines
  • I-kappa B Proteins
  • Interleukin-1
  • NF-kappa B
  • NFKBIA protein, human
  • Toll-Like Receptors
  • NF-KappaB Inhibitor alpha