LONDON - A consortium of scientists from five countries has announced the discovery of a genetic abnormality that leads to the rare disorder known as incontinentia pigmenti (IP).

The finding will lead to improved screening for families affected by the disease. It also will give added impetus to cell biologists studying the NF-kB activation pathway, because the gene responsible for IP encodes a molecule called the NF-kB essential modulator, or NEMO.

Sue Kenwrick, of the Wellcome Trust Centre for the Molecular Mechanism of Disease and a lecturer in the Department of Medicine at Cambridge University in Cambridge, UK, told BioWorld International: "NEMO is required for a very important cell pathway involved in cell death, cell survival, cell morphology and many other functions. The disease will help us understand the biology of this pathway, because it points to certain cells and tissues where the gene is needed, and the biology in turn will help us understand the particular clinical effects you get in the disease."

IP affects about one in every 10,000 females. In the UK, for example, there are an estimated 6,500 females with the disease. Affected males usually die before birth, while affected females suffer a range of symptoms that vary in severity. In females, the first sign of the disease is a blistering rash similar to that of chicken pox or herpes, shortly after birth. The rash may become warty, and streaks of brown pigment later appear. Eventually, these signs clear up, leaving pale scarred areas on the skin.

About 80 percent of IP sufferers have missing teeth, or malformed crowns. About 40 percent have retinal problems, caused by abnormal blood vessels in the eyes. In about 10 percent of cases there are more severe problems, such as neurological abnormalities, including mental retardation or seizures.

IP is an X-linked dominant disorder. Males who inherit the mutated gene on the X chromosome from their mother are so badly affected that they die before birth. Females who inherit one copy of the gene that causes IP are not so severely affected because their other (normal) copy of the X chromosome can compensate to some extent for the mutated version.

In females, the defect also is lethal to any cell that expresses the mutant gene. In any one cell, however, only one chromosome is actively expressing its genes at any one time. Some cells in females will therefore be expressing genes from the paternal copy while others will be expressing genes from the maternal copy. A cell in a female with IP that expresses genes on the affected copy of the X chromosome will therefore die. In any population of cells - say skin or blood - the place of these cells will be taken by those expressing the genes on the healthy copy of the X chromosome.

Kenwrick explained that the collaborative effort to find the gene responsible for IP came about with the encouragement of Susanne Emmerich, director of the National Incontinentia Pigmenti Foundation in the U.S. "She got all the scientists together at an international genetics meeting, and it was then that we decided it would be best to pool our expertise and resources rather than trying to find the gene independently."

The results are described in a paper published in the May 25, 2000, issue of Nature titled "Genomic rearrangement in NEMO impairs NF-kB activation and is a cause of incontinentia pigmenti." Research groups in France, Germany, Italy, the UK and the U.S. took part in the project.

Kenwrick said, "What we found was that 80 percent of females with IP carry the same mutation, which is a deletion of a section of the NEMO gene. Of the other 20 percent, at least half have other types of mutations in the same gene. The protein encoded by this gene is a very important one for many different functions. It is a "gateway" protein to many different pathways. Most of the mutations knock out the NF-kB activation pathway. As the NF-kB pathway is important for many cell types, this may be why the males die."

The discovery of the IP gene is very important for affected or potentially affected families, Kenwrick explained. As genetic diseases go, it is not uncommon and may be underdiagnosed. The NF-kB essential modulator is clearly a key gene in development, and crucial for cell survival. In addition, in the past it has been very difficult to counsel families with affected members because it can easily be mistaken for other diseases. Patients are, for example, sometimes treated inappropriately for diseases such as herpes.

"Now," Kenwrick said, "because most patients have the same mutation, it will be easy to set up screening programs to test for IP. This will be particularly useful where a neonate develops a rash but there is no family history of IP, and in cases where a woman is having repeated miscarriages, which may be due to carrying male fetuses with IP. Women with IP will also want to know how to manage their pregnancies, and what their risks are of having an affected child."

Kenwrick said, "Our immediate aim here in the UK is to get screening for IP into the health service. Each country will, of course, have to approach this challenge according to its own needs."