ERCC6

The ERCC6 gene provides instructions for making a protein commonly called Cockayne syndrome B (CSB) protein. This protein is involved in repairing damaged DNA and also appears to assist with transcription. Transcription is the process of making a blueprint of a gene, a required step for protein production. The CSB protein's role in transcription is not clearly understood. It might help to start this process and may monitor transcription progress.

The CSB protein specializes in repairing damaged DNA within active genes (those genes undergoing transcription). DNA can be damaged by several agents such as toxic compounds and ultraviolet (UV) rays from sunlight. If left uncorrected, DNA damage accumulates, eventually causing cell death. Normally, however, cells use several repair mechanisms to correct DNA damage before cell activities are impaired. One such mechanism involves the CSB protein. When DNA in active genes is damaged, the enzyme that carries out transcription (RNA polymerase) gets stuck, and the transcription 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 transcription after the damage is corrected.

Cockayne syndrome - caused by mutations in the ERCC6 gene

More than 20 ERCC6 mutations that cause Cockayne syndrome have been identified. Mutations in the ERCC6 gene have also been reported in individuals with combined features of Cockayne syndrome and another disorder called xeroderma pigmentosum. (Xeroderma pigmentosum is characterized by a wide variety of skin changes, from mild freckling to skin cancer, due to extreme sensitivity to sunlight.) Many ERCC6 mutations result in an abnormally short 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 not completely clear how ERCC6 mutations lead to Cockayne syndrome. The altered CSB protein probably hinders DNA repair and may be unable to assist with transcription. As a result, damaged DNA is not rapidly repaired, and transcription may be reduced. The accumulated DNA damage and altered transcription are assumed to cause impaired cell function and eventually, the death of cells in many organs. Increased cell death probably contributes to features of Cockayne syndrome such as growth failure and premature aging.

other disorders - associated with the ERCC6 gene

In a small number of cases, ERCC6 mutations have been reported in conditions other than Cockayne syndrome. One such condition is UV-sensitive syndrome, characterized by an abnormal sensitivity to sunlight (photosensitivity). As a result, people with this condition can sunburn easily and have freckled skin or unusual skin coloring (pigmentation). In the reported cases of UV-sensitive syndrome, the ERCC6 mutation appears to eliminate the presence of CSB protein. It remains unclear how an ERCC6 mutation leads to this syndrome. Without CSB protein, however, it is assumed that skin cells cannot repair DNA that is damaged by UV rays.

Another condition associated with an ERCC6 mutation is de Sanctis-Cacchione syndrome, which is a severe form of xeroderma pigmentosum that includes problems with the nervous system. The reported ERCC6 mutation appears to result in an altered version of the CSB protein that is half its normal size. Most likely, the smaller protein cannot function properly to assist with DNA repair, or it is unstable and rapidly breaks down.