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Gene dysfunction in human CdLS may result from abnormal genome folding

 18 May 2021   Research News

Genes, the blueprint of life, are stored in the form of DNA. Each cell in the human body contains around 2 metres of DNA, intricately arranged in the micron-sized space of the nucleus. The pattern of genome folding contributes to the regulation of gene expression.

The cohesin protein complex is a key player in the three-dimensional organisation of DNA. In humans, mutations in cohesin cause developmental abnormalities known as Cornelia de Lange Syndrome (CdLS). Patients with CdLS have symptoms that can include limb abnormalities, heart malformations, and epilepsy. All CdLS patients show a degree of intellectual disability, and many have autism spectrum disorder.

Using CdLS patient samples, researchers from the Lymphocyte Development Group at the MRC LMS have discovered that CdLS patient neurons have abnormal gene expression. Interestingly, the observed changes resemble those in patients with autism spectrum disorder. Reduced expression of cohesin in mouse neurons produced changes in gene expression that were highly similar to those observed in CdLS patients. Finally, the researchers showed that changes in gene activity caused by the loss of cohesin function were not permanent, and could in fact be rescued. This raises the question whether pharmaceutical intervention could be used to benefit CdLS patients and correct the abnormal gene activity.

Felix Weiss, lead author of the paper, discussed new possibilities stemming from this research:

“This work is the first ever analysis using CdLS patient tissue, and gives a brand new insight into the disease. Bringing together the worlds of clinical and basic biology has opened up exciting new avenues for future research in both CdLS and gene regulation.”

‘Neuronal genes deregulated in Cornelia de Lange Syndrome respond to removal and re-expression of cohesin’ was published on 18 May in Nature Communications. Read the full article here.