2.1. Xeroderma pigmentosum

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 total 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 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 xeroderma pigmentosum 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 xeroderma pigmentosum 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.