Xeroderma Pigmentosum
(XP) is caused by mutations in the XPA gene. At least 25
mutations in the XPA gene have been found to cause Xeroderma Pigmentosum.
Mutations in this gene are responsible for a very severe form of the disorder
that is more common in the Japanese population than in other populations. Most
Japanese people with Xeroderma Pigmentosum have the same XPA gene
mutation, which is written as IVS3AS,
G>C. This mutation prevents cells from producing any
functional XPA protein. Other XPA gene mutations, which have
been reported in Japan and elsewhere, result in the production of a defective
version of the XPA protein or greatly reduce the amount of this protein that is
made in cells.
A partial or complete
loss of the XPA protein prevents cells from repairing DNA damage normally. As a
result, abnormalities accumulate in DNA, causing cells to malfunction and
eventually to become cancerous or die. These problems with DNA repair cause
people with Xeroderma Pigmentosum (XP) to be extremely sensitive to UV rays
from sunlight. When UV rays damage genes that control cell growth and division,
cells can grow too fast and in an uncontrolled way. As a result, people with XP
have a greatly increased risk of developing cancer. These cancers occur most
frequently in areas of the body that are exposed to the sun, such as the skin
and eyes.
When XP is caused by XPA gene
mutations, it is often associated with progressive neurological abnormalities.
These nervous system problems include hearing loss, poor coordination,
difficulty walking, movement problems, loss of intellectual function,
difficulty swallowing and talking, and seizures. The neurological abnormalities
are thought to result from a buildup of DNA damage, although the brain is not
exposed to UV rays.
Researchers suspect
that other factors damage DNA in nerve cells. It is unclear why some people
with Xeroderma Pigmentosum develop neurological abnormalities and others do
not.
