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 NF-kappa B activation and resistance to TNF-induced apoptosis. Female mice heterozygous for Ikk gamma/Nemo deficiency develop a unique dermatopathy characterized by keratinocyte hyperproliferation, skin inflammation, hyperkeratosis, and increased apoptosis. Although Ikk gamma+/- females eventually recover, Ikk gamma- males die in utero. These symptoms and inheritance pattern are very similar to those of incontinentia pigmenti (IP), a human genodermatosis, synthenic with the IKK gamma/NEMO locus. Indeed, biopsies and cells from IP patients exhibit defective IKK gamma/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 IKK gamma/NEMO-deficient cells trigger an inflammatory reaction that eventually leads to their death.
Makris
C
C
Department of Pharmacology, University of California, San Diego, La Jolla 92093, USA.
Godfrey
V L
VL
Krähn-Senftleben
G
G
Takahashi
T
T
Roberts
J L
JL
Schwarz
T
T
Feng
L
L
Johnson
R S
RS
Karin
M
M
D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D002460:Cell Line; D018925:Chemokines / Q000235:genetics; D004195:Disease Models, Animal; D004303:Dosage Compensation, Genetic; D005260:Female; D005313:Fetal Death; D018390:Gene Targeting; D006579:Heterozygote; D006801:Humans; D051550:I-kappa B Kinase; D007184:Incontinentia Pigmenti / Q000235:genetics* / Q000473:pathology*; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism / Q000473:pathology; D013154:Spleen / Q000473:pathology; D013950:Thymus Gland / Q000473:pathology
D018925:Chemokines; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse