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 3

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Sequence of the IKBA gene in the patient and his relatives. (a) Schemati...
Sequence of the IKBA gene in the patient and his relatives. (a) Schematic representation of IκBα. The various functional/structural domains of the protein are shown. NH2, N-terminal; rPEST, repeated peptidic sequence rich in proline, glutamic acide, serine, and threonine (PEST); Ile, isoleucine. (b) Phosphoacceptor sites of IκB molecules and location of the patient’s mutation S32I. The two conserved serine residues that are phosphorylated by IKK in IκBα, IκBβ, and IκBε are boxed. Mutated Ser32 of patient P is indicated by an arrow. (c) Automated sequencing profile of genomic DNA showing the heterozygous C/T polymorphism at position 89 and the heterozygous G/T (S32I) disease-causing mutation at position 94 in our patient. The two heterozygous positions from left (position 89) to right (position 94) appear as N nucleotides.