Human Pigmentation Disorder Linked to Genetic Defect in Inflammatory Pathway

PI: Michael Karin
University of California, San Diego

Background: Incontinentia pigmenti (IP) is a genetic disorder characterized by unusual patterns of discolored skin. Males with this disorder usually die before birth, so females are the major patient group. In rare cases it can cause developmental abnormalities such as dwarfism and club foot. Although the skin abnormalities usually regress with age, in some individuals effects such as neurological problems and structural anamolies can persist throughout life. A team of researchers have identified genetic mutations in a critical component of the body's inflammation response as a key to understanding this disorder. They have also constructed a mouse model with this same genetic deficiency that mimics the human disease.

Advance: NFkB is a transcription factor that is a major regulator of immune responses stimulated by pro­inflammatory stimuli such as tumor necrosis factor (TNF), viruses, interleukin­1, and bacterial cell walls. NFkB also protects cells from TNF stimulated programmed cell death. NFkB normally resides in the cytoplasm where it is bound by an inhibitory protein called IkB. During a pro-inflammatory stimulus, IkB is phosphorylated by IkB kinase (IKK) which leads to the proteolysis of IkB and movement of NFkB into the nucleus allowing it to act as a transcription factor. IKK which is made up of three components: IKKa and IKKb catalytic subunits and the IKKy/NEMO regulatory subunit. A group of researchers found skin lesions in female mice heterozygous for IKKy/NEMO deficiency that were remarkably similar to IP.

Both IP in humans and IKKy/NEMO deficiency in mice are conditions linked to the X chromosome. IKKy/NEMO deficiency in male mice is a lethal condition with death occurring at around the twelfth day of gestation. Most human males with IP die prenatally and perinatally. IP in females is manifested by a blistering skin condition that eventually leaves the skin with pale streaks contrasted by areas of hyperpigmentation. The similarities in the two conditions prompted this team of investigators to look for expression of the IKK subunits in biopsies and fibroblasts of IP patients. As in the mice, female human tissue proved markedly deficient in IKKy/NEMO expression. A male fetus and newborn whose mother had a positive diagnosis for IP were completely lacking IKKy/NEMO expression.

Implications: This study definitively links incontinentia pigmenti with deficiency of IKKy/NEMO expression. This connection provides additional evidence for the importance of the IKK complex and NFkB for prevention of programmed cell death in mice and in humans. IKKy/NEMO deficient mice can be used as a model for studying the human disease IP and women with IP will be able to make more informed reproductive decisions. [Area of Emphasis: New Approaches to Pathogenesis; GPRA Goal: Add to the body of knowledge about normal and abnormal functions and behavior (Molecular and Cellular Systems)]

Citation: Makris C, Godfrey VL, Krahn-Senftleben G, Takahashi T, Roberts JL, Schwarz T, Feng L, Johnson RS, Karin M: Female mice heterozygous for IKK gamma/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorderincontinentia pigmenti. Mol Cell. 5: 969-979, 2000.