Female Mice Heterozygous for IKKγ/NEMO Deficiencies Develop a Dermatopathy Similar to the Human X-Linked Disorder Incontinentia Pigmenti

IKKγ/NEMO is the essential regulatory subunit of the IκB kinase (IKK), encoded by an X-linked gene in mice and humans. It is required for NF-κB activation and resistance to TNF-induced apoptosis. Female mice heterozygous for Ikkγ/Nemo deficiency develop a unique dermatopathy characterized by keratinocyte hyperproliferation, skin inflammation, hyperkeratosis, and increased apoptosis. Although Ikkγ +/− females eventually recover, Ikkγ − males die in utero. These symptoms and inheritance pattern are very similar to those of incontinentia pigmenti (IP), a human genodermatosis, synthenic with the IKKγ/NEMO locus. Indeed, biopsies and cells from IP patients exhibit defective IKKγ/NEMO expression but normal expression of IKK catalytic subunits. This unique self-limiting disease, the first to be genetically linked to the IKK signaling pathway, is dependent on X-chromosome inactivation. We propose that the IKKγ/NEMO-deficient cells trigger an inflammatory reaction that eventually leads to their death.