title: IKBKG (nuclear factor-kappa B essential modulator) mutation can be associated with opportunistic infection without impairing Toll-like receptor function.
abstract: BACKGROUND
  Patients with hypomorphic nuclear factor-kappaB essential modulator (NEMO) mutations have extensive phenotypic variability that can include atypical infectious susceptibility.
  
  
  OBJECTIVE
  This study may provide important insight into immunologic mechanisms of host defense.
  
  
  METHODS
  Immunologic evaluation, including studies of Toll-like receptor (TLR) function, was performed in a 6-month-old boy with normal ectodermal development who was diagnosed with Pneumocystis pneumonia and cytomegalovirus sepsis.
  
  
  RESULTS
  Genomic and cDNA sequencing demonstrated a novel NEMO missense mutation, 337G->A, predicted to cause a D113N (aspartic acid to asparagine) substitution in the first coiled-coil region of the NEMO protein. Quantitative serum immunoglobulins, lymphocyte subset numbers, and mitogen-induced lymphocyte proliferation were essentially normal. The PBMC responses to TLR ligands were also surprisingly normal, whereas natural killer cell cytolytic activity, T-cell proliferative responses to specific antigens, and T-cell receptor-induced NF-kappaB activation were diminished.
  
  
  CONCLUSIONS
  Unlike the unique NEMO mutation described here, the most commonly reported mutations are clustered at the 3' end in the tenth exon, which encodes a zinc finger domain. Because specific hypomorphic variants of NEMO are associated with distinctive phenotypes, this particular NEMO mutation highlights a dispensability of the region including amino acid 113 for TLR signaling and ectodysplasin A receptor function. This region is required for certain immunoreceptor functions as demonstrated by his susceptibility to infections as well as natural killer cell and T-cell defects.
authors.affiliation: Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA.
authors.forename: Bryn H
authors.initials: BH
authors.lastname: Salt
authors.forename: Julie E
authors.initials: JE
authors.lastname: Niemela
authors.forename: Rahul
authors.initials: R
authors.lastname: Pandey
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hanson
authors.forename: Raquel P
authors.initials: RP
authors.lastname: Deering
authors.forename: Ralph
authors.initials: R
authors.lastname: Quinones
authors.forename: Ashish
authors.initials: A
authors.lastname: Jain
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
authors.forename: Erwin W
authors.initials: EW
authors.lastname: Gelfand
mesh_terms: D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics*; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000097:blood; D007223:Infant; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D009154:Mutation; D016328:NF-kappa B / Q000096:biosynthesis / Q000378:metabolism; D009894:Opportunistic Infections / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000502:physiology*
chemical_list: C491731:IKBKG protein, human; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D016328:NF-kappa B; D051193:Toll-Like Receptors; D051550:I-kappa B Kinase