Female mice heterozygous for IKK gamma/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti

IKK gamma/NEMO is the essential regulatory subunit of the I kappa B kinase (IKK), encoded by an X-linked gene in mice and humans. It is required for N F-kappa B activation and resistance to TNF-induced apoptosis. Female mice h eterozygous for Ikk gamma/Nemo deficiency develop a unique dermatopathy cha racterized by keratinocyte hyperproliferation, skin inflammation, hyperkera tosis, and increased apoptosis. Although Ikk gamma(+/-) females eventually recover, Ikk gamma(-) males die in utero. These symptoms and inheritance pa ttern are very similar to those of incontinentia pigmenti (IP), a human gen odermatosis, synthenic with the IKK gamma/NEMO locus. Indeed, biopsies and cells from IP patients exhibit defective IKK gamma/NEMO expression but norm al expression of IKK catalytic subunits. This unique self-limiting disease, the first to be genetically linked to the IKK signaling pathway, is depend ent on X-chromosome inactivation. We propose that the IKK gamma/NEMO-defici ent cells trigger an inflammatory reaction that eventually leads to their d eath.