title: A novel mutation in NFKBIA/IKBA results in a degradation-resistant N-truncated protein and is associated with ectodermal dysplasia with immunodeficiency.
abstract: Alterations in nuclear factor kappa B (NF-kappaB) essential modulator (NEMO; HUGO-approved symbol IKBKG) underlie most cases of ectodermal dysplasia with immune deficiency (EDI), a human disorder characterized by anhidrosis with diminished immunity. EDI has also been associated with a single heterozygous mutation at position Ser32 of the NF-kappaB inhibitor IkappaBalpha, one of two phosphorylation sites that are essential for targeting IkappaBalpha for proteasomal degradation and hence for activation of NF-kappaB. We report a novel heterozygous nonsense mutation in the IKBA (HUGO-approved symbol, NFKBIA) gene of a 1-year-old male child with EDI that introduces a premature termination codon at position Glu14. An in-frame methionine downstream of the nonsense mutation allows for reinitiation of translation. The resulting N-terminally truncated protein lacks both serine phosphorylation sites and inhibits NF-kappaB signaling by functioning as a dominant negative on NF-kappaB activity in lymphocytes and monocytes. These findings support the scanning model for translation initiation in eukaryotes and confirm the critical role of the NF-kappaB in the human immune response.
authors.affiliation: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Lopez-Granados
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Keenan
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Kinney
authors.forename: Harvey
authors.initials: H
authors.lastname: Leo
authors.forename: Neal
authors.initials: N
authors.lastname: Jain
authors.forename: Chi A
authors.initials: CA
authors.lastname: Ma
authors.forename: Ralph
authors.initials: R
authors.lastname: Quinones
authors.forename: Erwin W
authors.initials: EW
authors.lastname: Gelfand
authors.forename: Ashish
authors.initials: A
authors.lastname: Jain
mesh_terms: D000595:Amino Acid Sequence; D018389:Codon, Nonsense; D004476:Ectodermal Dysplasia / Q000235:genetics*; D006801:Humans; D051550:I-kappa B Kinase / Q000737:chemistry / Q000235:genetics; D020672:I-kappa B Proteins / Q000235:genetics*; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000276:immunology; D014176:Protein Biosynthesis; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D018389:Codon, Nonsense; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D051550:I-kappa B Kinase