What happens differently in the brain development of CdLS people with a mutation in NIPBL?

Our brain processes information and determines our daily functioning. Growing and developing a brain requires great precision in creating, laying out and positioning nerve cells. Researchers will build human mini-brains to analyse what goes wrong when NIPBL, a key regulator of our genes, malfunctions.

Dr K.S. (Kerstin) Wendt (Erasmus MC), Dr D.L.C. (Debbie) Van den Berg (Erasmus MC), Dr M. (Mehrnaz) Ghazvini (Erasmus MC), Dr L.A. (Leonie) Menke (Amsterdam UMC) and Dr S.A. (Sylvia) Huisman (Amsterdam UMC) will investigate this through the study:

Modelling neurodevelopmental defects and mosaicism in CdLS using human brain organoids
Modelling neurodevelopmental defects and mosaicism in CdLS using human brain organoids .

Kerstin and Debbie explained to us (Marloes, Dennis and Gerritjan ; parents of Milou and Rai) what they will do in this study.

Cause of Cornelia de Lange syndrome

We already know that several genes play a role in Cornelia de Lange syndrome (CdLS). The illustration below shows that NIPBL, the gene altered (mutated) in the vast majority of CdLS cases, plays a role in the so-called Cohesin Complex.

Changes in the brain

We know that in people with CdLS we often see the following:

  • smaller head circumference
  • intellectual disability
  • problems with speech/language development
  • behavioural problems
  • epilepsy

So it is interesting to better understand ;

  • How are the nerve cells in the brain connected?
  • How are these connections when there are healthy as well as 'diseased' nerve cells (mosaicism)?
  • Which genes in the brain are all turned ON and OFF (regulated) by NIPBL?
  • How does this affect brain development?

How can we look at this?

A recent discovery has made it possible to recreate a piece of nerve tissue like the brain using 'pluripotent stem cells'. We call this 'brain organoids', which are nerve cells in 3D or 'mini-brains'.

For example, by taking a piece of skin from people with CdLS (who have a NIPBL mutation and a mosaic NIPBL mutation in particular), the researchers can "reprogramme pluripotent stem cells" from that tissue to become, for example, a heart muscle, blood stem cells, a pancreas but also nerve cells from the brain.

Making a piece of the brain in a dish

Thus, researchers can thus make brains in a dish, which they can study well for the influence of a mosaic NIPBL mutation.

We are very impressed with this study and we wish Kerstin, Debbie, Mehrnaz, Leonie and Sylvia a successful study. And, of course, we hope that after this study we will again understand more about the impact of a NIPBL mutation on brain development in conjunction with neurodevelopmental features (such as small brain, intellectual disability, different social development, behavioural problems and epilepsy), so that we can better guide and treat people with CdLS to function as pleasantly as possible and have the best possible life. 

Of course, the researchers cannot do this without good cooperation with people with CdLS, their parents and families. The researchers like to maintain close contact with an advisory group of the CdLS association (Marloes, Dennis, Gerritjan) and keep the families informed together with them.

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