title: Human nuclear factor kappa B essential modulator mutation can result in immunodeficiency without ectodermal dysplasia.
abstract: BACKGROUND
  Many receptors rely on the appropriate activation of nuclear factor (NF) kappa B to induce cellular function. This process depends critically on the phosphorylation of the inhibitor of NF-kappa B (I kappa B) by the I kappa B kinase. This targets I kappa B for ubiquitination and degradation, allowing NF-kappa B to translocate to the nucleus, where it can direct transcription. Hypomorphic human mutations affecting one I kappa B kinase component, the NF-kappa B essential modulator (NEMO), result in impaired signaling from receptors required for ectodermal development and immune function. Male subjects with these mutant NEMO molecules have an X-linked syndrome known as ectodermal dysplasia with immunodeficiency, which is characterized by severe infections, with herpesviruses, bacteria, and mycobacterial susceptibility.
  
  
  OBJECTIVE
  We sought to genetically and biochemically characterize a patient with a mutant NEMO molecule without ectodermal abnormalities.
  
  
  METHODS
  We evaluated NEMO in a patient who had immunodeficiency and atypical mycobacterial infection but normal ectoderm.
  
  
  RESULTS
  We identified a novel NEMO mutant causing immunodeficiency without ectodermal dysplasia. The mutation, which altered the exon 9 splice site, was present in cells of ectodermal and hematopoetic origin and resulted in a heterogeneous mixture of mutant and wild-type cDNA species. Immunologic function was variably impaired, with reduced CD40-induced B-cell proliferation, partially reduced NF-kappa B p65 nuclear translocation, and variable Toll-like receptor-induced TNF production. This variability might be explained by an inconsistent ratio of mutant to wild-type NEMO. The lack of any ectodermal phenotype, however, suggested a separation in the hematopoetic and ectodermal function of NEMO that leads to NF-kappa B activation.
  
  
  CONCLUSIONS
  Mutation of the gene encoding NEMO can result in immunodeficiency without ectodermal dysplasia.
authors.affiliation: Division of Immunology, Children's Hospital of Philadelphia, Pa., USA.
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
authors.forename: Ofer
authors.initials: O
authors.lastname: Levy
authors.forename: Scott R
authors.initials: SR
authors.lastname: Brodeur
authors.forename: Konrad
authors.initials: K
authors.lastname: Krzewski
authors.forename: Rene M
authors.initials: RM
authors.lastname: Roy
authors.forename: Julie E
authors.initials: JE
authors.lastname: Niemela
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Fleisher
authors.forename: Francisco A
authors.initials: FA
authors.lastname: Bonilla
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
mesh_terms: D000293:Adolescent; D002352:Carrier Proteins; D004476:Ectodermal Dysplasia / Q000235:genetics / Q000276:immunology*; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000276:immunology; D006801:Humans; D051550:I-kappa B Kinase; D007113:Immunity, Innate; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology; D008297:Male; D009154:Mutation; D011506:Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C491731:IKBKG protein, human; D011506:Proteins; D051550:I-kappa B Kinase