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Human Molecular Genetics, 2002, Vol. 11, No. 20 2371-2375
© 2002 Oxford University Press

The NF-{kappa}B signalling pathway in human diseases: from incontinentia pigmenti to ectodermal dysplasias and immune-deficiency syndromes

Asma Smahi1,*, Gilles Courtois2, Smail Hadj Rabia1, Rainer Döffinger3, Christine Bodemer1, Arnold Munnich1, Jean-Laurent Casanova3 and Alain Israël2

1Département de Génétique et Unité de Recherches sur les Handicaps Génétiques de l'Enfant INSERM UR-393, Hôpital Necker, 149 rue de Sèvres, 75743 Paris Cedex 15, 2Unité de Biologie Moléculaire de l'Expression Génique, FRE 2364 CNRS, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris Cedex 15 and 3Unité de Génétique Humaine des maladies infectieuses, INSERM UR-550, Faculté de Médecine Necker, 156 rue de Vaugirard, 75730 Paris Cedex 15, France

Received July 10, 2002; Accepted July 15, 2002

The transcription factor NF-{kappa}B regulates the expression of numerous genes controlling the immune and stress responses, inflammatory reaction, cell adhesion, and protection against apoptosis. Incontinentia pigmenti (IP) is the first genetic disorder to be ascribed to NF-{kappa}B dysfunction. IP is an X-linked dominant genodermatosis antenatally lethal in males. A complex rearrangement of the NEMO (NF-{kappa}B essential modulator) gene accounts for 85% of IP patients, and results in undetectable NEMO protein and absent NF-{kappa}B activation. On the other hand, hypohidrotic/anhidrotic ectodermal dysplasia (HED/EDA) has been ascribed to at least three genes also involved in NF-{kappa}B activation: ectodysplasin (EDA1), EDA-receptor (EDAR) and EDAR-associated death domain (EDARADD). During hair follicle morphogenesis, EDAR is activated by ectodysplasin, and uses EDARADD as an adapter to build a signal transducing complex that leads to NF-{kappa}B activation. Hence, several forms of HED/EDA also result from impaired activation of the NF-{kappa}B cascade. Finally, hypomorphic NEMO mutations have been found to cause anhidrotic ectodermal dysplasia with immunodeficiency (EDA–ID), whilst stop codon mutations cause a more severe phenotype associating EDA–ID with osteopetrosis and lymphoedema (OL–EDA–ID). The immunological and infectious features observed in patients result from impaired NF-{kappa}B signalling, including cellular response to LPS, IL-1ß, IL-18, TNF-{alpha}, Tlr2 and CD40 ligand. Consistently, mouse knockout models have shown the essential role of NF-{kappa}B in the immune, inflammatory and apoptotic responses. Unravelling the molecular bases of other forms of EDA not associated with mutations in NEMO will possibly implicate other components of the NF-{kappa}B signalling pathway.

* To whom correspondence should be addressed. Tel: +33 144495161; Fax: +33 147348514; Email: smahi{at}necter.fr


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