title: A novel gain-of-function IKBA mutation underlies ectodermal dysplasia with immunodeficiency and polyendocrinopathy.
abstract: OBJECTIVE
  This study reports the identification of a novel heterozygous IKBA missense mutation (p.M37K) in a boy presenting with ectodermal dysplasia with immunodeficiency (EDA-ID) who had wild type IKBKG gene encoding NEMO. Our aim was to characterize the clinical course of this IκB-α gain-of-function mutant and to investigate if the p.M37K substitution affects NF-κB activation by interfering with IκB-α degradation, thus impairing NF-κB signaling and causing the EDA-ID phenotype.
  
  
  METHODS
  NF-κB signaling was evaluated by measuring IκB-α degradation in patient fibroblasts. In addition, transiently transfected HeLa cells expressing either the M37K-mutant IκB-α allele, the previously characterized S36A-mutant IκB-α allele, or wild type IκB-α were evaluated for IκB-α degradation and NF-κB nuclear translocation following stimulation with TNF-α.
  
  
  RESULTS
  Clinical findings revealed a classical ectodermal dysplasia phenotype complicated by recurrent mucocutaneous candidiasis, hypothyroidism, hypopituitarism, and profound combined immunodeficiency with decreased numbers of IL-17 T cells. IκB-α degradation after TNF-α and TLR agonist stimulation was abolished in patient fibroblasts as well as in HeLa cells expressing M37K-IκB-α similar to cells expressing S36A-IκB-α resulting in impaired nuclear translocation of NF-κB and reduced NF-κB dependent luciferase activity compared to cells expressing wild type IκB-α. Patient whole blood cells failed to secrete IL-6 in response to IL-1ß, Pam2CSK4, showed reduced responses to LPS and PMA/Ionomycin, and lacked IL-10 production in response to TNF-α.
  
  
  CONCLUSIONS
  The novel heterozygous mutation p.M37K in IκB-α impairs NF-κB activation causing autosomal dominant EDA-ID with an expanded clinical phenotype.
authors.affiliation: Department of Pediatrics, University of Washington and Seattle Children's Research Institute, Seattle, WA 98101-1304, USA.
authors.forename: Lena F
authors.initials: LF
authors.lastname: Schimke
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Rieber
authors.forename: Stacey
authors.initials: S
authors.lastname: Rylaarsdam
authors.forename: Otávio
authors.initials: O
authors.lastname: Cabral-Marques
authors.forename: Nicholas
authors.initials: N
authors.lastname: Hubbard
authors.forename: Anne
authors.initials: A
authors.lastname: Puel
authors.forename: Laura
authors.initials: L
authors.lastname: Kallmann
authors.forename: Stephanie Anover
authors.initials: SA
authors.lastname: Sombke
authors.forename: Gundula
authors.initials: G
authors.lastname: Notheis
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Schwarz
authors.forename: Birgit
authors.initials: B
authors.lastname: Kammer
authors.forename: Tomas
authors.initials: T
authors.lastname: Hökfelt
authors.forename: Reinald
authors.initials: R
authors.lastname: Repp
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Bernd H
authors.initials: BH
authors.lastname: Belohradsky
authors.forename: Michael H
authors.initials: MH
authors.lastname: Albert
authors.forename: Hans D
authors.initials: HD
authors.lastname: Ochs
authors.forename: Ellen D
authors.initials: ED
authors.lastname: Renner
authors.forename: Troy R
authors.initials: TR
authors.lastname: Torgerson
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism*; D002675:Child, Preschool; D016207:Cytokines / Q000276:immunology; D004476:Ectodermal Dysplasia / Q000276:immunology*; D005347:Fibroblasts / Q000276:immunology*; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D007153:Immunologic Deficiency Syndromes / Q000276:immunology*; D007223:Infant; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D020125:Mutation, Missense / Q000235:genetics; D016884:Polyendocrinopathies, Autoimmune / Q000276:immunology*; D059748:Proteolysis; D058504:Th17 Cells / Q000276:immunology; D019076:Transgenes / Q000235:genetics
chemical_list: D016207:Cytokines; D051550:I-kappa B Kinase