-
Anne Puel,
Janine Reichenbach,
Jacinta Bustamante,
Cheng-Lung Ku,
Jacqueline Feinberg,
Rainer Döffinger, Marion Bonnet,
Orchidée Filipe-Santos,
Ludovic de Beaucoudrey,
Anne Durandy,
Gerd Horneff,
Francesco Novelli,
Volker Wahn,
Asma Smahi,
Alain Israel,
Tim Niehues,
Jean-Laurent Casanova
[show abstract]
[hide abstract]
ABSTRACT: Amorphic mutations in the NF- kappa B essential modulator (NEMO) cause X-dominant incontinentia pigmenti, which is lethal in males in utero, whereas hypomorphic mutations cause X-recessive anhidrotic ectodermal dysplasia with immunodeficiency, a complex developmental disorder and life-threatening primary immunodeficiency. We characterized the NEMO mutation 110_111insC, which creates the most-upstream premature translation termination codon (at codon position 49) of any known NEMO mutation. Surprisingly, this mutation is associated with a pure immunodeficiency. We solve this paradox by showing that a Kozakian methionine codon located immediately downstream from the insertion allows the reinitiation of translation. The residual production of an NH(2)-truncated NEMO protein was sufficient for normal fetal development and for the subsequent normal development of skin appendages but was insufficient for the development of protective immune responses.
The American Journal of Human Genetics 05/2006; 78(4):691-701. · 10.60 Impact Factor
-
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
[show abstract]
[hide abstract]
ABSTRACT: X-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.
Journal of Clinical Investigation 11/2003; 112(7):1108-15. · 15.39 Impact Factor
-
Capucine Picard,
Anne Puel, Marion Bonnet,
Cheng-Lung Ku,
Jacinta Bustamante,
Kun Yang,
Claire Soudais,
Stéphanie Dupuis,
Jacqueline Feinberg,
Claire Fieschi, [......],
Rajivi Rucker,
Thomas R Hawn,
Alan Aderem,
Haysam Tufenkeji,
Soichi Haraguchi,
Noorbibi K Day,
Robert A Good,
Marie-Anne Gougerot-Pocidalo,
Adrian Ozinsky,
Jean-Laurent Casanova
[show abstract]
[hide abstract]
ABSTRACT: Members of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) superfamily share an intracytoplasmic Toll-IL-1 receptor (TIR) domain, which mediates recruitment of the interleukin-1 receptor-associated kinase (IRAK) complex via TIR-containing adapter molecules. We describe three unrelated children with inherited IRAK-4 deficiency. Their blood and fibroblast cells did not activate nuclear factor kappaB and mitogen-activated protein kinase (MAPK) and failed to induce downstream cytokines in response to any of the known ligands of TIR-bearing receptors. The otherwise healthy children developed infections caused by pyogenic bacteria. These findings suggest that, in humans, the TIR-IRAK signaling pathway is crucial for protective immunity against specific bacteria but is redundant against most other microorganisms.
Science 04/2003; 299(5615):2076-9. · 31.20 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: CYLD deubiquitinase has been originally defined as a tumor suppressor based exclusively on genetic findings. Indeed, inactivation of CYLD in humans results in familial cylindromatosis and multiple trichoepithelioma, two pathologies characterized by the development of tumors originating specifically from the skin appendages. A set of recent publications has revealed that recurrent inactivation of CYLD occurs through diverse mechanisms in several forms of cancer, unequivocally confirming its tumor suppressor function. This property is associated with the critical role played by CYLD in negatively regulating several signaling pathway, among them the NF-κB signaling pathway.
Medecine sciences: M/S 27(6-7):626-31. · 0.64 Impact Factor
