ERCC8

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.

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).