title: A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency.
abstract: X-linked anhidrotic ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is caused by hypomorphic mutations in the gene encoding NEMO/IKKgamma, the regulatory subunit of the IkappaB kinase (IKK) complex. IKK normally phosphorylates the IkappaB-inhibitors of NF-kappaB at specific serine residues, thereby promoting their ubiquitination and degradation by the proteasome. This allows NF-kappaB complexes to translocate into the nucleus where they activate their target genes. Here, we describe an autosomal-dominant (AD) form of EDA-ID associated with a heterozygous missense mutation at serine 32 of IkappaBalpha. This mutation is gain-of-function, as it enhances the inhibitory capacity of IkappaBalpha by preventing its phosphorylation and degradation, and results in impaired NF-kappaB activation. The developmental, immunologic, and infectious phenotypes associated with hypomorphic NEMO and hypermorphic IKBA mutations largely overlap and include EDA, impaired cellular responses to ligands of TIR (TLR-ligands, IL-1beta, and IL-18), and TNFR (TNF-alpha, LTalpha1/beta2, and CD154) superfamily members and severe bacterial diseases. However, AD-EDA-ID but not XL-EDA-ID is associated with a severe and unique T cell immunodeficiency. Despite a marked blood lymphocytosis, there are no detectable memory T cells in vivo, and naive T cells do not respond to CD3-TCR activation in vitro. Our report highlights both the diversity of genotypes associated with EDA-ID and the diversity of immunologic phenotypes associated with mutations in different components of the NF-kappaB signaling pathway.
authors.affiliation: Unité de Biologie Moléculaire de l'Expression Génique, Centre National de la Recherche Scientifique URA 2582, Institut Pasteur, Paris, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Courtois
authors.forename: Asma
authors.initials: A
authors.lastname: Smahi
authors.forename: Janine
authors.initials: J
authors.lastname: Reichenbach
authors.forename: Rainer
authors.initials: R
authors.lastname: Döffinger
authors.forename: Caterina
authors.initials: C
authors.lastname: Cancrini
authors.forename: Marion
authors.initials: M
authors.lastname: Bonnet
authors.forename: Anne
authors.initials: A
authors.lastname: Puel
authors.forename: Christine
authors.initials: C
authors.lastname: Chable-Bessia
authors.forename: Shoji
authors.initials: S
authors.lastname: Yamaoka
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Feinberg
authors.forename: Sophie
authors.initials: S
authors.lastname: Dupuis-Girod
authors.forename: Christine
authors.initials: C
authors.lastname: Bodemer
authors.forename: Susanna
authors.initials: S
authors.lastname: Livadiotti
authors.forename: Francesco
authors.initials: F
authors.lastname: Novelli
authors.forename: Paolo
authors.initials: P
authors.lastname: Rossi
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Alain
authors.initials: A
authors.lastname: Israël
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Françoise
authors.initials: F
authors.lastname: Le Deist
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
mesh_terms: D002648:Child; D004476:Ectodermal Dysplasia / Q000235:genetics*; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000235:genetics*; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D008297:Male; D009154:Mutation; D016328:NF-kappa B / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human