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EnglishX-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., S.A. (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.
| Tipologia: | Articolo su rivista |
| Citazione: | Courtois G., S.A. (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. |
| Lingua: | English |
| Settore Scientifico Disciplinare: | Settore MED/38 - Pediatria Generale e Specialistica |
| Revisione (peer review): | Sì, ma tipo non specificato |
| Tipo: | Articolo |
| Rilevanza: | Rilevanza internazionale |
| Digital Object Identifier (DOI): | http://dx.doi.org/10.1172/JCI200318714 |
| Stato di pubblicazione: | Pubblicato |
| Data di pubblicazione: | 2003 |
| Titolo: | A hypermorphic I kappa B alpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency |
| Autori: | |
| Autori: | 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 J.-L. |
| Appare nelle tipologie: | 01 - Articolo su rivista |
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http://hdl.handle.net/2108/57601
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