ERCC6

The ERCC6 gene provides instructions for making a protein commonly called the Cockayne syndrome B (CSB) protein. This protein is involved in repairing damaged DNA and appears to assist with gene transcription, which is the first step in protein production. Although the role of the CSB protein is not clearly understood, this protein might help to start (initiate) gene transcription and then monitor its progress.

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, normal 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.

Cockayne syndrome - caused by mutations in the ERCC6 gene

More than 60 ERCC6 gene mutations that cause Cockayne syndrome have been identified. Many of these mutations lead to the production of an abnormally short version of the CSB protein that cannot function properly. Other mutations change one of the building blocks (amino acids) used to make the CSB protein, which also results in a malfunctioning protein.

It is unclear how ERCC6 gene mutations lead to Cockayne syndrome. 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, and gene transcription may be disrupted. These abnormalities impair cell function and eventually lead to the death of cells in many organs and tissues. The increased cell death likely contributes to features of Cockayne syndrome, such as growth failure and premature aging.

UV-sensitive syndrome - caused by mutations in the ERCC6 gene

UV-sensitive syndrome, which is a disorder characterized by sun sensitivity, can also result from mutations in the ERCC6 gene. People with this condition sunburn easily and have freckled skin or other changes in skin coloring (pigmentation). At least one ERCC6 gene mutation has been found to cause UV-sensitive syndrome. This 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 exactly how a loss of the CSB protein causes UV-sensitive syndrome.

Genetics Home Reference provides information about age-related macular degeneration, which is also associated with changes in the ERCC6 gene.