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University of California, San Diego (UCSD) researchers studying, in mice, the molecular machinery of an important signaling pathway inadvertently discovered the gene responsible for a mysterious human congenital disease.

The researchers genetically engineered mice to lose the function of the IKK-gamma gene to study its impact. They noticed that male offspring died during development, and the females that survived developed prominent skin abnormalities that appeared in phases. After an exhaustive search of the literature, they found a little-known human disease called incontinentia pigmenti (IP), whose symptoms fit like a glove with those seen in the mice.

Above shows  normal (left) and IKKy/IP live female mice (right).  The left panel show a dorsal view and the right panel a ventral view of day 6 mice.  Notice the red and blistery skin of the IKKy/IP female mouse on the right.  This skin abnormality is also found in female IP patients and may last several months in these patients. By one month of age, these mice fully recover.

 

The research findings, featured on the cover of the June 16 issue of the journal Molecular Cell, describe the first human disease found to be linked to the I-kappa-B kinase (IKK) signaling pathway, the master switch for the body’s immune and inflammatory responses, and for programmed cell death.

“We have a nearly perfect mouse model of this disease,” said Constantin Makris, Ph.D., principal author on the paper and a postdoctoral fellow in the UCSD lab of Michael Karin, Ph.D., who discovered the IKK complex. “This is important because IP has been a mystery that nobody really understood. Now we can study it thoroughly and develop diagnostic and screening tests.”

This link has been confirmed by an international consortium of human geneticists who have been working on mapping this gene for the last five to 10 years. The consortium reported finding the gene, they named NEMO, less than a month ago in the May 25 issue of Nature.

By day 10, the IKKy/IP mice develop darkened areas in a swirled "marble cake" pattern (middle image), and wart-like lesions (bottom image) which eventually fall off.  Similar features are also seen in female IP patients.

IP is a relatively rare genetic disease whose most prominent features appear in stages and involve the skin and its derivatives (hair, teeth and nails). The first stage consists of a red rash, blisters and boils, which may last up to several months. The second stage involves development of wart-like lesions that look like pustules. In the third stage the skin develops darkened areas in a swirled (“marble cake”) pattern. The fourth stage involves scarring, and is seen in adolescents and adults as pale, hairless patches or streaks.

Once most patients reach adulthood (late teen and beyond), the skin changes fade and may not be visible to the casual observer. Girls born with IP often have abnormally shaped teeth, bald patches on the scalp, and missing or deformed nails. Males who inherit the defective gene do not survive. IP is estimated to affect from one in 10,000 to one in 100,000. For further detail, visit the National Incontinentia Pigmenti Foundation Web site: http://imgen.bcm.tmc.edu/NIPF.

“This disorder is heartbreaking for parents,” said Makris. “But it now will be possible to develop genetic tests that will be helpful in family planning. For example, a woman could choose to undergo in-vitro fertilization and have only those eggs implanted that are unaffected by the genetic condition.”

Since Karin’s discovery in late 1996 of IKK and its three sub-units – alpha, beta and gamma – showing that the IKK complex is responsible for controlling the body’s inflammatory response, pharmaceutical companies worldwide have been working on the development of drugs to inhibit IKK. Such drugs are likely to be potent anti-inflammatory and anti-cancer agents. The IKK-gamma knockout mouse will be critical in testing the new drugs for side effects.

“This paper is an outstanding example of the importance of research using genetically engineered mice,” said Michael Karin, Ph.D., professor of pharmacology and director of the Cancer Biology Program at UCSD Cancer Center. “The knockout mouse is probably the most powerful tool we have for understanding the function of novel genes.”

A molecular biologist, Karin is one of the “hottest biomedical researchers of the 1990s” as listed by Science Watch, a publication that tracks trends and performance in basic research. Since 1981, more than 70 of his papers have been cited well over 100 times each, and several have been cited more than 1,000 times each.

Besides Karin and Makris, co-authors are Takayuki Takahashi of UCSD School of Medicine; Virginia L. Godfrey, University of North Carolina, Chapel Hill; Jaclyn L. Roberts, State University of New York, an obstetrician who provided cell lines from male IP fetuses; Gertraud Krahn-Senftleben, University of Ulm, Germany, and Thomas Schwarz, University Muenster, Germany, both dermatologists who provided tissue samples; Lili Feng, Scripps Research Institute; and Randall S. Johnson, UCSD.

The research was supported by the National Institutes of Health (National Institute of Allergy and Infectious Diseases, National Institute of Environmental Health Sciences), and the California Cancer Research Program.

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