Trichothiodystrophy

At least one variant (also called a mutation) in the ERCC3 gene appears to be a rare cause of trichothiodystrophy. This condition affects many parts of the body. The hallmark of trichothiodystrophy is hair that is sparse and easily broken. The ERCC3 gene variant causes the photosensitive form of the condition, which is characterized by an extreme sensitivity to UV rays from sunlight.

The ERCC3 gene variant known to cause trichothiodystrophy changes one protein building block (amino acid) in the XPB protein; specifically, it replaces the amino acid threonine with the amino acid proline at protein position 119 (written as Thr119Pro or T119P). This variant probably makes the TFIIH complex unstable and reduces its ability to 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, likely result from problems with the transcription of genes needed for normal development before and after birth.

Unlike 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 ERCC3 gene affect a person's cancer risk and others do not.

Xeroderma pigmentosum

At least one variant in the ERCC3 gene also appears to be a rare cause of 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.

The ERCC3 gene variant that causes xeroderma pigmentosum changes one amino acid in the XPB protein. Specifically, the variant replaces the amino acid phenylalanine with the amino acid serine at protein position 99 (written as Phe99Ser or F99S). This variant greatly reduces the ability of the TFIIH complex to repair damaged DNA. As damage builds up in DNA, cells malfunction and eventually become cancerous or die.

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.

In addition to sun sensitivity, xeroderma pigmentosum is sometimes associated with progressive neurological abnormalities. In affected individuals with the Phe99Ser variant, neurological abnormalities have been relatively mild and have included hearing loss and poor coordination. Studies suggest that the neurological abnormalities associated with this condition 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.

Other disorders

Several variants in the ERCC3 gene can cause features of both xeroderma pigmentosum and another condition related to defective DNA repair called Cockayne syndrome. When this combination of features occurs in the same individual, it is known as xeroderma pigmentosum/Cockayne syndrome (XP/CS) complex. People with XP/CS complex may have extreme sun sensitivity, an increased risk of skin cancer, short stature, hearing loss, poor coordination, and intellectual disability.

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 ERCC3 gene variants affect the stability and function of the TFIIH complex in different ways. These variations may account for the different features of xeroderma pigmentosum, trichothiodystrophy, and XP/CS complex.