UV-sensitive syndrome is a condition that is characterized by sensitivity to the ultraviolet (UV) rays in sunlight. Even a small amount of sun exposure can cause a sunburn in affected individuals. In addition, these individuals can have freckles, dryness, or changes in coloring (pigmentation) on sun-exposed areas of skin after repeated exposure. Some people with UV-sensitive syndrome have small clusters of enlarged blood vessels just under the skin (telangiectasia), usually on the cheeks and nose. Although UV exposure can cause skin cancers, people with UV-sensitive syndrome do not have an increased risk of developing these forms of cancer compared with the general population.

UV-sensitive syndrome appears to be a rare condition; only a small number of affected individuals have been reported in the scientific literature. However, this condition may be underdiagnosed.

UV-sensitive syndrome can result from mutations in the ERCC6 gene (also known as the CSB gene), the ERCC8 gene (also known as the CSA gene), or the UVSSA gene. These genes provide instructions for making proteins that are involved in repairing damaged DNA. DNA can be damaged by UV rays from the sun and by toxic chemicals, radiation, and unstable molecules called free radicals. Cells are usually able to fix DNA damage before it causes problems. If left uncorrected, DNA damage accumulates, which causes cells to malfunction and can lead to cell death.

Cells have several mechanisms to correct DNA damage. The CSB, CSA, and UVSSA proteins are involved in one mechanism that repairs damaged DNA within active genes (those genes undergoing gene transcription, the first step in protein production). When DNA in active genes is damaged, the enzyme that carries out gene transcription (RNA polymerase) gets stuck, and the process stalls. Researchers think that the CSB, CSA, and UVSSA proteins help remove RNA polymerase from the damaged site, so the DNA can be repaired.

Mutations in the ERCC6, ERCC8, or UVSSA genes lead to the production of an abnormal protein or the loss of the protein. If any of these proteins is not functioning normally, skin cells cannot repair DNA damage caused by UV rays, and transcription of damaged genes is blocked. However, it is unclear exactly how abnormalities in these proteins cause the signs and symptoms of UV-sensitive syndrome.

Normal Function

The ERCC6 gene provides instructions for making a protein called Cockayne syndrome B (CSB). This protein is involved in repairing damaged DNA and appears to assist with gene transcription, which is the first step in protein production.

DNA can be damaged by ultraviolet (UV) rays from the sun and by toxic chemicals, radiation, and unstable molecules called free radicals. If left uncorrected, DNA damage accumulates, which causes cells to malfunction and can lead to cell death. Although DNA damage occurs frequently, cells are usually able to fix it before it can cause problems. Cells have several mechanisms to correct DNA damage; one such mechanism involves the CSB protein. This protein specializes in repairing damaged DNA within active genes (those genes undergoing gene transcription). When DNA in active genes is damaged, the enzyme that carries out gene transcription (RNA polymerase) gets stuck, and the process stalls. Researchers think that the CSB protein helps remove RNA polymerase from the damaged site, so the DNA can be repaired. The CSB protein may also assist in restarting gene transcription after the damage is corrected.

Health Conditions Related to Genetic Changes

Cockayne syndrome

More than 60 ERCC6 gene mutations that cause Cockayne syndrome have been identified. This rare condition includes a variety of features, including an abnormally small head size (microcephaly), very slow growth resulting in short stature, delayed development, and an increased sensitivity to sunlight (photosensitivity).

Many of the ERCC6 gene mutations that cause Cockayne syndrome lead to the production of an abnormally short version of the CSB protein that cannot function properly. Other mutations change single building blocks (amino acids) in the CSB protein, which also results in a malfunctioning protein.

The mechanism by which ERCC6 gene mutations lead to Cockayne syndrome is not well understood. The altered CSB protein probably hinders DNA repair and may be unable to assist with gene transcription. As a result, damaged DNA is not fixed, which disrupts gene transcription and prevents the normal production of proteins. These abnormalities impair cell function and eventually lead to the death of cells in many organs and tissues. Faulty DNA repair underlies photosensitivity in affected individuals, and researchers suspect that it also contributes to the other features of Cockayne syndrome. It is unclear how ERCC6 gene mutations cause all of the varied features of this condition.

UV-sensitive syndrome

At least one mutation in the ERCC6 gene can cause UV-sensitive syndrome, a condition characterized by unusual sensitivity to UV rays from the sun. People with UV-sensitive syndrome sunburn easily and have freckled skin or other changes in skin coloring (pigmentation). The known mutation, which is written as Arg77Ter or R77X, replaces the amino acid arginine with a premature stop signal at position 77 in the CSB protein. If any protein is produced, it is abnormally short and quickly broken down. Without this protein, skin cells cannot repair DNA damage caused by UV rays, and transcription of damaged genes is blocked. However, it is unclear how a loss of the CSB protein causes UV-sensitive syndrome. Additionally, it is unknown why the Arg77Ter mutation causes photosensitivity without the other features of Cockayne syndrome (described above).

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Other Names for This Gene

• ARMD5
• CKN2
• COFS
• CSB
• ERCC6_HUMAN
• excision repair cross-complementation group 6
• RAD26
• Rad26 (yeast) homolog

Genomic Location

Normal Function

The ERCC8 gene provides instructions for making a protein called Cockayne syndrome A (CSA), which is involved in repairing damaged DNA. DNA can be damaged by ultraviolet (UV) rays from the sun and by toxic chemicals, radiation, and unstable molecules called free radicals. The damage caused by these agents can block vital cell activities such as gene transcription, which is the first step in protein production. If left uncorrected, DNA damage accumulates, which causes cells to malfunction and can lead to cell death.

Although DNA damage occurs frequently, cells are usually able to fix it before it can cause problems. Cells have several mechanisms to correct DNA damage; one such mechanism involves the CSA protein. This protein specializes in repairing damaged DNA within active genes (those genes undergoing gene transcription). However, its specific role in this process is unclear. The CSA protein interacts with other proteins, probably to identify areas of damaged DNA.

Health Conditions Related to Genetic Changes

Cockayne syndrome

Researchers have identified more than 30 ERCC8 gene mutations that can cause Cockayne syndrome. This rare condition includes a variety of features, including an abnormally small head size (microcephaly), very slow growth resulting in short stature, delayed development, and an increased sensitivity to sunlight (photosensitivity).

Some of the ERCC8 gene mutations result in the production of an abnormally short version of the CSA protein that cannot function properly. Other mutations change one of the building blocks (amino acids) used to make the CSA protein, which also results in a malfunctioning protein.

The mechanism by which ERCC8 gene mutations lead to Cockayne syndrome is not well understood. The altered CSA protein probably disrupts DNA repair. As a result, damaged DNA is not fixed, which disrupts gene transcription and prevents the normal production of proteins. These abnormalities impair cell function and eventually lead to the death of cells in many organs and tissues. Faulty DNA repair underlies photosensitivity in affected individuals, and researchers suspect that it also contributes to the other features of Cockayne syndrome. It is unclear how ERCC8 gene mutations cause all of the varied features of this condition.

UV-sensitive syndrome

At least one mutation in the ERCC8 gene can cause UV-sensitive syndrome, a condition characterized by unusual sensitivity to UV rays from the sun. People with UV-sensitive syndrome sunburn easily and have freckled skin or other changes in skin coloring (pigmentation). The known mutation replaces the amino acid tryptophan with the amino acid cysteine at position 361 in the CSA protein (written as Trp361Cys or W361C). Although the effect of this change on the function of the protein is unknown, it somehow prevents cells from repairing DNA damage caused by UV rays, and transcription of damaged genes is blocked. It is unclear exactly how an abnormal CSA protein causes the signs and symptoms of UV-sensitive syndrome. Additionally, it is unknown why the Trp361Cys mutation causes photosensitivity without the other features of Cockayne syndrome (described above).

Other Names for This Gene

• CKN1
• Cockayne syndrome 1 (classical)
• Cockayne syndrome 1 protein
• Cockayne syndrome, type A
• CSA
• ERCC8_HUMAN
• excision repair cross-complementation group 8
• excision repair cross-complementing rodent repair deficiency, complementation group 8

Genomic Location

Normal Function

The UVSSA gene provides instructions for making a protein that is involved in repairing DNA damaged by ultraviolet (UV) rays from the sun. The damage can block vital cell activities such as gene transcription, which is the first step in protein production. If left uncorrected, DNA damage accumulates, which causes cells to malfunction and can lead to cell death.

Cells have several mechanisms to correct DNA damage. The UVSSA protein is involved in one mechanism that repairs damaged DNA within active genes (those genes undergoing gene transcription). When DNA in active genes is damaged, the enzyme that carries out gene transcription (RNA polymerase) gets stuck, and the process stalls. Researchers think that the UVSSA protein helps remove RNA polymerase from the damaged site, so the DNA can be repaired. Part of the UVSSA protein's role in this process is to ensure that another important protein called CSB is not broken down by exposure to UV rays.

Health Conditions Related to Genetic Changes

UV-sensitive syndrome

Mutations in the UVSSA gene cause UV-sensitive syndrome, which is a disorder characterized by sun sensitivity. People with this condition sunburn easily and have freckled skin or other changes in skin coloring (pigmentation). At least three UVSSA gene mutations have been identified, and these mutations eliminate the production of the UVSSA protein. Without this protein, skin cells cannot repair DNA damage caused by UV rays, and transcription of damaged genes is blocked. However, it is unclear exactly how a loss of the UVSSA protein causes the signs and symptoms of UV-sensitive syndrome.

Other Names for This Gene

• KIAA1530
• UV-stimulated scaffold protein A
• UVSS3
• UVSSA_HUMAN

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.