Female Mice Heterozygous for IKK gamma/NEMO Deficiencies Develop a Dermatopathy Similar to the Human X-linked Disorder Incontinentia Pigmenti

Mol Cell. 2000 Jun;5(6):969-79. doi: 10.1016/s1097-2765(00)80262-2.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Cell Division
  • Cell Line
  • Chemokines / genetics
  • Disease Models, Animal
  • Dosage Compensation, Genetic
  • Female
  • Fetal Death
  • Gene Targeting
  • Heterozygote*
  • Humans
  • I-kappa B Kinase
  • Incontinentia Pigmenti / genetics*
  • Incontinentia Pigmenti / pathology*
  • Inflammation / genetics
  • Inflammation / pathology
  • Liver / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology*
  • Signal Transduction
  • Skin / metabolism
  • Skin / pathology
  • Spleen / pathology
  • Thymus Gland / pathology

Substances

  • Chemokines
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • Chuk protein, mouse
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Ikbkb protein, mouse
  • Ikbke protein, mouse