Knocking out NEMO

Abstract

A flurry of recent papers have shed new light on the role of the NF-κB signalling pathway, and provided a molecular understanding of the basis for a rare genetic disease, familial incontinentia pigmenti (IP) 1 Smahi A. et al. Genomic rearrangement in NEMO impairs NF-κB activation and is a cause of incontinentia pigmenti. Nature. 2000; 405: 466-472 Crossref PubMed Scopus (576) Google Scholar , 2 Makris C. et al. Female mice heterozygous for IKKγ/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti. Mol. Cell. 2000; 5: 969-979 Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar , 3 Schmidt-Supprian M. et al. NEMO/IKKγ-deficient mice model incontinentia pigmenti. Mol. Cell. 2000; 5: 981-992 Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar , 4 Rudolph D. et al. Severe liver degeneration and lack of NF-κB activation in NEMO/IKKγ-deficient mice. Genes Dev. 2000; 14: 854-862 PubMed Google Scholar , an X-linked dominant genetic disorder. In affected males, IP leads to prenatal lethality, whereas in females, it causes multiple congenital defects that affect the skin, hair, nails, teeth, eyes and central nervous system. The skin defects appear in several cutaneous stages: perinatal inflammatory vesicles are followed by verrucous patches, and these hyperkeratotic lesions disappear, leaving a distinctive pattern of hyperpigmented whorls and subsequent dermal scarring. Counterselection of cells that express the mutated gene results in extremely skewed patterns of X inactivation in female patients. The IP locus has been mapped to Xq28, near the gene for Factor VIII.