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.

Courtois, G., Smahi, A., Reichenbach, J., Doffinger, R., Cancrini, C., Bonnet, M., et al. (2003). A hypermorphic I kappa B alpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. THE JOURNAL OF CLINICAL INVESTIGATION, 112(7), 1108-1115 [10.1172/JCI200318714].

A hypermorphic I kappa B alpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency

CANCRINI, CATERINA;ROSSI, PAOLO;
2003-01-01

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.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/38 - Pediatria Generale e Specialistica
English
CD40 ligand; complementary DNA; cytokine; genomic DNA; I kappa B alpha; I kappa B kinase; I kappa B kinase gamma; immunoglobulin enhancer binding protein; interleukin 18; interleukin 1beta; T lymphocyte receptor; tumor necrosis factor alpha; tumor necrosis factor receptor; unclassified drug; CHUK protein, human; I kappa B; I kappa B beta; IKBKB protein, human; IKBKE protein, human; lymphocyte antigen receptor; protein serine threonine kinase; anhidrosis; anhidrotic ectodermal dysplasia; article; autosomal dominant disorder; case report; cellular immunity; controlled study; disease association; ectodermal dysplasia; gene; gene mutation; human; human cell; IKBA gene; immune deficiency; immunogenetics; infant; male; priority journal; T lymphocyte; X chromosome linked disorder; child; genetic transcription; genetics; immunology; mutation; physiology; signal transduction; Child; Ectodermal Dysplasia; Humans; I-kappa B Kinase; I-kappa B Proteins; Immunologic Deficiency Syndromes; Male; Mutation; NF-kappa B; Protein-Serine-Threonine Kinases; Receptor-CD3 Complex, Antigen, T-Cell; Signal Transduction; T-Lymphocytes; Transcription, Genetic; Tumor Necrosis Factor-alpha
Courtois, G., Smahi, A., Reichenbach, J., Doffinger, R., Cancrini, C., Bonnet, M., et al. (2003). A hypermorphic I kappa B alpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. THE JOURNAL OF CLINICAL INVESTIGATION, 112(7), 1108-1115 [10.1172/JCI200318714].
Courtois, G; Smahi, A; Reichenbach, J; Doffinger, R; Cancrini, C; Bonnet, M; Puel, A; Chable Bessia, C; Yamaoka, S; Feinberg, J; Dupuis Girod, S; Bodemer, C; Livadiotti, S; Novelli, F; Rossi, P; Fischer, A; Israel, A; Munnich, A; Le Deist, F; Casanova, Jl
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/57601
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