A hypermorphic IκBα mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1108-1115
Number of pages8
JournalJournal of Clinical Investigation
Volume112
Issue number7
DOIs
Publication statusPublished - Oct 2003

ASJC Scopus subject areas

  • Medicine(all)

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    Courtois, G., Smahi, A., Reichenbach, J., Döffinger, 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., Israël, A., Munnich, A., Le Deist, F., & Casanova, J. L. (2003). A hypermorphic IκBα mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. Journal of Clinical Investigation, 112(7), 1108-1115. https://doi.org/10.1172/JCI200318714