Gene found to be important for embryonic development

An international study led by the University of Bonn has identified a gene that plays an important role in the development of the human embryo; if it is altered, malformations of various organ systems can result. The study has been published in the Journal of Medical Genetics.

The researchers tracked down the gene when they studied two individuals — a man and his niece — with congenital malformations. When the team looked at the genetic make-up of the family members, they came across an anomaly: a gene called SHROOM4 was altered in affected individuals compared to healthy individuals.

SHROOM4 was already familiar from another context: it was known to play a key role in brain function, whereby mutations can result in intellectual impairment, epileptic seizures and behavioural abnormalities. With the team’s findings indicating that the gene may play a broader role in embryonic organ development, the scientists searched internationally for other cases in which abnormalities in the SHROOM4 gene had also been found. This led them to four more affected individuals from three families, all of whom had the SHROOM4 gene altered but not always in the same way.

This did not necessarily clarify whether SHROOM4 variants were actually responsible for the malformations, but there is an animal that has a very similar gene: the zebrafish. The zebrafish serves as a model organism in many genetic studies today — partially because the skin of its larvae is almost transparent, which makes it easy to observe the animal’s embryonic development under the light microscope.

The researchers almost completely inactivated SHROOM4 in zebrafish larvae, the result of which was that the animals showed malformations similar to those seen in the patients. If, on the other hand, larvae with SHROOM4 switched off were injected with the intact human genetic material, they developed almost normally.

“This shows first that they absolutely need a functional SHROOM4 for healthy development, and second, that the human gene can still take over the function of the fish gene,” said Dr Gabriel Dworschak, a physician at the University Hospital Bonn.

The team now wants to find out which part the gene plays in embryonic development. According to Dworschak, “We assume that it is needed for very basic processes in the cell. It’s hard to explain otherwise why changes in the same gene cause such a variety of symptoms.”

The researchers acknowledge that we still don’t fully understand how humans or animals develop from fertilised ova, as the ovum has the ability to form any type of tissue in the organism — bone, skin, muscle or the brain. Its daughter cells are genetically identical to it; so in principle they should be able to do the same. But at a very early stage, certain programs are activated in their cells that irrevocably determine their developmental fate.

This process must be coordinated down to the finest detail, because only then it is ensured that the eyes form in the appropriate spot on the face, while other cells very close by differentiate into the nasal cartilage. Surprisingly, however, there does not appear to be any conductor wielding the baton.

“Our study is a small piece of the mosaic to this picture, which is still largely incomplete,” Dworschak said.

Image caption: Two live zebrafish larvae in which the SHROOM4 gene was switched off. Corresponding malformations are recognisable (small eyes, small heads, anomalies of the intestine, indications of heart defects). Image ©Dr Caroline Kolvenbach and Dr Gabriel Dworschak/University of Bonn

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