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

Courtois, Gilles, Smahi, Asma, Reichenbach, Janine, Döffinger, Rainer, Cancrini, Caterina, Bonnet, Marion ORCID: https://orcid.org/0000-0002-7559-2413, Puel, Anne, Chable-Bessia, Christine, Yamaoka, Shoji, Feinberg, Jacqueline, Dupuis-Girod, Sophie, Bodemer, Christine, Livadiotti, Susanna, Novelli, Francesco, Rossi, Paolo, Fischer, Alain, Israël, Alain, Munnich, Arnold, Le Deist, Françoise and Casanova, Lean-Laurent 2003. A hypermorphic IκBα mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. Journal of Clinical Investigation 112 (7) , pp. 1108-1115. 10.1172/JCI18714

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	American Society for Clinical Investigation
ISSN:	0021-9738
Last Modified:	09 Nov 2022 10:11
URI:	https://orca.cardiff.ac.uk/id/eprint/138624

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