ERCC2

Many variants (also called mutations) in the ERCC2 gene have been found to cause trichothiodystrophy. This condition affects many parts of the body. The hallmark of trichothiodystrophy is hair that is sparse and easily broken. Affected children may develop severe hip degeneration.

Variants in this gene are the most common cause of the photosensitive form of the condition, which is characterized by an extreme sensitivity to UV rays from sunlight.

Studies suggest that the ERCC2 gene variants responsible for trichothiodystrophy reduce the amount of functional TFIIH complex in cells. Without enough of this complex, cells cannot effectively repair DNA damage caused by UV radiation. These problems with DNA repair cause people with the photosensitive form of trichothiodystrophy to be extremely sensitive to sunlight. Other features of the condition, such as slow growth, intellectual disability, and brittle hair, probably result from problems with the transcription of genes needed for normal development before and after birth.

Unlike another condition called xeroderma pigmentosum (described below), trichothiodystrophy is not associated with an increased risk of skin cancer. Researchers are working to determine why some variants in the ERCC2 gene affect a person's cancer risk and others do not.

More than two dozen variants in the ERCC2 gene have been identified in people with xeroderma pigmentosum. This condition is characterized by an extreme sensitivity to UV rays from sunlight. This condition mostly affects the eyes and areas of skin exposed to the sun.

Variants in the ERCC2 gene are the second most common cause of xeroderma pigmentosum in the United States. The ERCC2 gene variants responsible for xeroderma pigmentosum prevent the TFIIH complex from repairing damaged DNA effectively. As damage builds up in DNA, cells malfunction and eventually become cancerous or die. These problems with DNA repair cause people with xeroderma pigmentosum to be extremely sensitive to UV rays. 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 ERCC2 gene variants, 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.

Rarely, variants in the ERCC2 gene can cause features of both xeroderma pigmentosum and trichothiodystrophy in the same individual. This condition is known as xeroderma pigmentosum/trichothiodystrophy (XP/TTD) complex. ERCC2 gene variants have also been identified in a few individuals with signs and symptoms of both xeroderma pigmentosum and another condition related to defective DNA repair called Cockayne syndrome. This combination of features is known as xeroderma pigmentosum/Cockayne syndrome (XP/CS) complex.

Researchers are uncertain how variants in this single gene can cause several different disorders with a wide variety of signs and symptoms. Studies suggest that different ERCC2 gene variants affect the stability and function of the TFIIH complex in different ways. Variants also have varied effects on the interaction between the XPD protein and other proteins that make up the TFIIH complex. These variants may account for the different features of xeroderma pigmentosum, trichothiodystrophy, and XP/TTD and XP/CS complexes.