The
transcription factor NF-kappaB 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-kappaB dysfunction. IP is an X-linked dominant genodermatosis antenatally lethal in males. A complex rearrangement of the NEMO (
NF-kappaB essential modulator) gene accounts for 85% of IP patients, and results in undetectable NEMO
protein and absent
NF-kappaB activation. On the other hand, hypohidrotic/
anhidrotic ectodermal dysplasia (HED/EDA) has been ascribed to at least three genes also involved in
NF-kappaB 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-kappaB activation. Hence, several forms of HED/EDA also result from impaired activation of the
NF-kappaB 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-kappaB signalling, including cellular response to LPS, IL-1beta,
IL-18,
TNF-alpha, Tlr2 and
CD40 ligand. Consistently, mouse knockout models have shown the essential role of
NF-kappaB 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-kappaB signalling pathway.