Cockayne syndrome is caused by genetic mutations that impair the body’s ability to repair damaged DNA, specifically affecting a process called transcription-coupled nucleotide excision repair (TC-NER). This repair mechanism is crucial for fixing DNA damage that occurs during normal cellular activities and from environmental factors like ultraviolet (UV) light. When these repair systems fail due to mutations, cells accumulate DNA damage, leading to the symptoms of Cockayne syndrome.
At the core, Cockayne syndrome results from mutations in genes responsible for producing proteins that detect and repair DNA damage. The two most commonly affected genes are **ERCC6 (also known as CSB)** and **ERCC8 (also known as CSA)**. These genes encode proteins that help recognize DNA damage and recruit the repair machinery to the site of injury. When these proteins are defective or missing, the repair process is disrupted, causing cells to malfunction or die prematurely.
Because DNA damage accumulates, especially in cells that are actively transcribing genes, tissues that rely heavily on cell division and repair—such as the brain, skin, eyes, and ears—are particularly affected. This leads to the hallmark features of Cockayne syndrome, including growth failure, premature aging, sensitivity to sunlight, hearing loss, vision problems, and neurological decline.
The syndrome is inherited in an **autosomal recessive** pattern, meaning a child must inherit two defective copies of the gene (one from each parent) to develop the disorder. Parents who carry one mutated gene typically do not show symptoms but can pass the mutation to their children.
The DNA repair defect in Cockayne syndrome is distinct from other related disorders like xeroderma pigmentosum (XP) and trichothiodystrophy (TTD), which also involve problems with nucleotide excision repair but differ in the specific genes affected and clinical symptoms. For example, XP patients have a higher risk of skin cancer due to defective global genome repair, while Cockayne syndrome patients primarily suffer from neurological and developmental problems without a marked increase in cancer risk.
In summary, Cockayne syndrome is caused by inherited mutations in genes critical for repairing DNA damage during gene transcription. This failure to fix DNA damage leads to cellular dysfunction and the progressive symptoms seen in affected individuals.
