title: 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.
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.
  
  
  CONCLUSIONS
  This is the first description of immune deficiency resulting from low expression of a normal NEMO protein.
authors.affiliation: Division of Immunology, Children's Hospital Boston, Boston, Mass 02115, USA.
authors.forename: Jana L
authors.initials: JL
authors.lastname: Mooster
authors.forename: Caterina
authors.initials: C
authors.lastname: Cancrini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Simonetti
authors.forename: Paolo
authors.initials: P
authors.lastname: Rossi
authors.forename: Gigliola
authors.initials: G
authors.lastname: Di Matteo
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Romiti
authors.forename: Silvia
authors.initials: S
authors.lastname: Di Cesare
authors.forename: Luigi
authors.initials: L
authors.lastname: Notarangelo
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
authors.forename: Douglas R
authors.initials: DR
authors.lastname: McDonald
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics*; D002648:Child; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D051550:I-kappa B Kinase / Q000032:analysis / Q000235:genetics*; D020672:I-kappa B Proteins / Q000378:metabolism; D007153:Immunologic Deficiency Syndromes / Q000209:etiology* / Q000235:genetics; D053583:Interleukin-1beta / Q000494:pharmacology; D008297:Male; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D022821:RNA Splice Sites; D012333:RNA, Messenger / Q000032:analysis; D051193:Toll-Like Receptors / Q000502:physiology
chemical_list: D020121:5' Untranslated Regions; D016207:Cytokines; D020672:I-kappa B Proteins; C491731:IKBKG protein, human; D053583:Interleukin-1beta; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D022821:RNA Splice Sites; D012333:RNA, Messenger; D051193:Toll-Like Receptors; D000072000:NF-KappaB Inhibitor alpha; D051550:I-kappa B Kinase