A hypermorphic IκBα mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency
Gilles Courtois, … , Françoise Le Deist, Jean-Laurent Casanova
Gilles Courtois, … , Françoise Le Deist, Jean-Laurent Casanova
Published October 1, 2003
Citation Information: J Clin Invest. 2003;112(7):1108-1115. https://doi.org/10.1172/JCI18714.
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A hypermorphic IκBα 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/IKKγ, the regulatory subunit of the IκB kinase (IKK) complex. IKK normally phosphorylates the IκB-inhibitors of NF-κB at specific serine residues, thereby promoting their ubiquitination and degradation by the proteasome. This allows NF-κB 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 IκBα. This mutation is gain-of-function, as it enhances the inhibitory capacity of IκBα by preventing its phosphorylation and degradation, and results in impaired NF-κB 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-1β, and IL-18), and TNFR (TNF-α, LTα1/β2, 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-κB signaling pathway.

Authors

Gilles Courtois, Asma Smahi, Janine Reichenbach, Rainer Döffinger, Caterina Cancrini, Marion Bonnet, Anne Puel, Christine Chable-Bessia, Shoji Yamaoka, Jacqueline Feinberg, Sophie Dupuis-Girod, Christine Bodemer, Susanna Livadiotti, Francesco Novelli, Paolo Rossi, Alain Fischer, Alain Israël, Arnold Munnich, Françoise Le Deist, Jean-Laurent Casanova

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Figure 2

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Specific defect of IκBα degradation in patient’s fibroblasts treated wit...
Specific defect of IκBα degradation in patient’s fibroblasts treated with TNF-α (a) IKK kinase assay and Western blot analysis of IκBα degradation. Phosphorylated IκBα exhibits a retarded migration and is indicated on the right. GST-IκBα, a fusion between gluthatione-S-Transferase and the first 72 amino acids of IκBα, was used as a substrate for IKK. GST, gluthatione-S-transferase. (b) Western blot analysis of IKK subunits in fibroblasts from a healthy control, NEMO-mutated patient X-EDA-ID and IκBα-mutated patient P. (c) Western blot analysis of IκBα Ser32 phosphorylation after TNF-α stimulation. Circled P, phosphorylated. (d) Time course analysis of TNF-induced IκBα, IκBβ, and IκBε degradation, as detected by Western blot. Results from one representative experiment are shown.