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 theNational Academy of Sciences.