title: Heterozygous N-terminal deletion of IkappaBalpha results in functional nuclear factor kappaB haploinsufficiency, ectodermal dysplasia, and immune deficiency.
abstract: 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.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Immunology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: McDonald
authors.forename: Jana L
authors.initials: JL
authors.lastname: Mooster
authors.forename: Malathi
authors.initials: M
authors.lastname: Reddy
authors.forename: Erawati
authors.initials: E
authors.lastname: Bawle
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Secord
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
mesh_terms: D021581:Active Transport, Cell Nucleus; D002648:Child; D018389:Codon, Nonsense; D016207:Cytokines / Q000096:biosynthesis; D004476:Ectodermal Dysplasia / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics* / Q000378:metabolism; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D007375:Interleukin-1 / Q000494:pharmacology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000502:physiology*; D010766:Phosphorylation; D051193:Toll-Like Receptors / Q000502:physiology
chemical_list: D018389:Codon, Nonsense; D016207:Cytokines; D020672:I-kappa B Proteins; D007375:Interleukin-1; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D051193:Toll-Like Receptors; D000072000:NF-KappaB Inhibitor alpha