Cockayne syndrome study alters treatment research focus

23 September 2014

Brain cells

Image: Brain cells

Researchers at Cancer Research UK's London Research Institute (now part of the Francis Crick Institute)  have made a breakthrough in understanding a severe genetic disorder called Cockayne syndrome, with important implications for treatment.

Dr Jesper Svejstrup explained: "Cockayne syndrome is a very severe inherited disorder. Patients display a range of symptoms, with the most severe indicating various brain malfunctions.

"Because the mutated genes that cause the disease are involved in repair of DNA damage, especially in the active regions of the genome, it has always been assumed that CS is caused by defective DNA repair."

Now Dr Svejstrup's team has found that, in fact, CS appears to be caused by a failure of neuronal - or brain - cells to develop correctly and be maintained in a healthy state.

This, in turn, is due to a failure of correct gene expression in the CS cells: the CS genes are important for correct gene expression. Most genes in CS cells are expressed correctly, but around 5 to 10 per cent are either under- or over-expressed, and these include important neuronal genes that may give rise to the disease.

For the research, the scientists studied cell lines lacking the CS genes (derived from CS patients) and tissue from deceased patients from the brain bank at the US National Institutes of Health.

Commenting on the findings, Dr Svejstrup said: "Whereas much of the clinical research into potential CS treatments has been focussed on somehow curbing or correcting the DNA repair defects of CS cells, it is now clear that much greater focus should be put on restoring the gene regulatory networks that control neuronal development.

"We saw defective regulation of certain well-studied substances that promote brain growth in CS patient tissue and cells. This has implications for therapy that are, fortunately, already being explored in other rare neurologic diseases, as well as by my own laboratory in the case of CS."

The paper, Dysregulation of gene expression as a cause of Cockayne syndrome neurological disease, is published in the Proceedings of the National Academy of Sciences.

  • Refuting previous assumptoms, researchers have discovered that a severe genetic disorder called Cockayne syndrome is caused by a failure of brain cells to develop correctly and be maintained in a healthy state. Research into treatments has been focused on the previous assumption that  the disease was caused by defective repair of DNA. The new study changes this focus. 
  • Cockayne syndrome is characterised by poor growth, small head circumference, premature aging, sensitivity to sunlight, moderate to profound developmental and neurological delays and a shortened lifespan. Symptom severity and rate of progression vary significantly between people affected. 
  • The scientists, from Cancer Research UK's London Research Institute, worked with colleagues at University College London, Harvard Medical School in Boston, USA, and the National Institutes of Health in Bethesda, USA.