Cockayne syndrome (CS), also called Neill-Dingwall syndrome, is a rare and fatal autosomal recessive neurodegenerative disorder characterized by growth failure, impaired development of the nervous system, abnormal sensitivity to sunlight (photosensitivity), eye disorders and premature aging. Failure to thrive and neurological disorders are criteria for diagnosis, while photosensitivity, hearing loss, eye abnormalities, and cavities are other very common features. Problems with any or all of the internal organs are possible. It is associated with a group of disorders called leukodystrophies, which are conditions characterized by degradation of neurological white matter. The underlying disorder is a defect in a DNA repair mechanism. Unlike other defects of DNA repair, patients with CS are not predisposed to cancer or infection. Cockayne syndrome is a rare but destructive disease usually resulting in death within the first or second decade of life. The mutation of specific genes in Cockayne syndrome is known, but the widespread effects and its relationship with DNA repair is yet to be well understood.It is named after English physician Edward Alfred Cockayne (1880–1956) who first described it in 1936 and re-described in 1946. Neill-Dingwall syndrome was named after Mary M. Dingwall and Catherine A. Neill. These two scientists described the case of two brothers with Cockayne syndrome and asserted it was the same disease described by Cockayne. In their article, the two contributed to the signs of the disease through their discovery of calcifications in the brain.
If either the ERCC6 or the ERCC8 gene is altered (as in Cockayne Syndrome), DNA damage encountered during transcription isnt repaired, causing RNA polymerase to stall at that location, interfering with gene expression. As the unrepaired DNA damage accumulates, progressively more active gene expression is impeded, leading to malfunctioning cells or cell death, which likely contributes to the signs of Cockayne Syndrome such as premature aging and neuronal hypomyelination. Mechanism
In contrast to cells with normal repair capability, CSA and CSB deficient cells are unable to preferentially repair cyclobutane pyrimidine dimers induced by the action of ultraviolet (UV) light on the template strand of actively transcribed genes. This deficiency reflects the loss of ability to perform the DNA repair process known as transcription coupled nucleotide excision repair (TC-NER).Within the damaged cell, the CSA protein normally localizes to sites of DNA damage, particularly inter-strand cross-links, double-strand breaks and some monoadducts. CSB protein is also normally recruited to DNA damaged sites, and its recruitment is most rapid and robust as follows: interstrand crosslinks > double-strand breaks > monoadducts > oxidative damage. CSB protein forms a complex with another DNA repair protein, SNM1A (DCLRE1A), a 5 – 3 exonuclease, that localizes to inter-strand cross-links in a transcription dependent manner. The accumulation of CSB protein at sites of DNA double-strand breaks occurs in a transcription dependent manner and facilitates homologous recombinational repair of the breaks.