The NF-κB signalling pathway in human diseases: From incontinentia pigmenti to ectodermal dysplasias and immune-deficiency syndromes

Abstract

The transcription factor NF-κB regulates the expression of numerous genes controlling the immune and stress responses, inflammatory reaction, cell adhesion, a nd protection against apoptosis. Incontinentia pigmenti (IP) is the first genetic disorder to be ascribed to NF-κB dysfunction. IP is an X-linked dominant genodermatosis antenatally lethal in males. A complex rearrangement of the NEMO (NF-κB essential modulator) gene accounts for 85% of IP patients, and results in undetectable NEMO protein and absent NF-κB activation. On the other hand, hypohidrotic/anhidrotic ectodermal dysplasia (HED/EDA) has been ascribed to at least three genes also involved in NF-κB 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-κB activation. Hence, several forms of HED/EDA also result from impaired activation of the NF-κB 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-κB signalling, including cellular response to LPS, IL-1β, IL-18, TNF-α, Tlr2 and CD40 ligand. Consistently, mouse knockout models have shown the essential role of NF-κB 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-κB signalling pathway.