An international study led by the University of Bonn Faculty of Medicine has identified a gene that plays an important role in the development of the human embryo. If it is disturbed, malformations of various organ systems can occur. The gene arose very early in evolution. It also exists in zebrafish, for example, and performs a similar function there. The results have already been published in the Journal of Medical Genetics.
The researchers tracked down the gene when they studied two people with birth defects.
It was a man and his niece. Both had malformed kidneys, urinary tracts and esophagus, and the man also had a malformed right arm and heart.”
Dr Gabriel Dworschak
The doctor at the Children’s University Hospital Bonn conducts research on rare genetic diseases at the Institutes for Human Anatomy and Genetics. When the team looked at the genetic makeup of family members, they found an abnormality: a gene called SHROOM4 was altered in affected people compared to healthy people.
SHROOM4 was already familiar from another context: it was known to play a key role in brain function. Mutations can result in intellectual impairment, epileptic seizures, and behavioral abnormalities. “Our findings indicated, however, that it may play a broader role in embryonic organ development,” explains Dworschak.
The Bonn team searched internationally for other cases in which abnormalities in the SHROOM4 gene had also been found, and were successful: “Together with our cooperation partners, this led us to four more affected individuals from three families,” says the Prof. Dr. Heiko. Reutter, who has since moved from the University Hospital Bonn to the University of Erlangen-Nuremberg. “They all had the SHROOM4 gene altered, but not always in the same way.”
Zebrafish also need SHROOM4
However, 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. It serves as a model organism in many genetic studies today, and not just because it is easy to maintain in a species-appropriate manner and reproduce rapidly: the skin of its larvae is almost transparent. This facilitates the observation of the embryonic development of the animals under the light microscope. “Here at the University Hospital we have the advantage that the research group led by Prof. Dr. Benjamin Odermatt from the Institute for Neuroanatomy works a lot with zebrafish,” highlights Dr. Caroline Kolvenbach, who was also involved in the study of SHROOM4. . “This experience was useful in our study.”
The researchers almost completely inactivated SHROOM4 in the larvae. The animals then showed malformations similar to those observed in the patients. If, on the other hand, larvae with knockout SHROOM4 are injected with intact human genetic material, they develop 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,” emphasizes Dworschak.
The team now wants to find out what role the gene plays in embryonic development. “We assume that it is needed for very basic processes in the cell,” says Dworschak. “It’s hard to explain otherwise why changes in the same gene cause a variety of symptoms.”
Small piece in the mosaic of an extremely complex painting
How a mouse, dog, or human develops from a fertilized egg is not yet fully understood. This is because the egg has the ability to form any type of tissue in the body, be it bone, skin, muscle or brain. His daughter cells are genetically identical to him; 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 smallest detail. Because this is the only way to ensure that the eyes form in the right place on the face, while other very close cells differentiate into the nasal cartilage. Surprisingly, however, there is no director wielding the baton. It’s like a Lego spaceship is assembling itself, only infinitely more complicated. “Our study is a small piece of the mosaic of this image, which is still largely incomplete,” says Dworschak.
Participating institutions and funding:
In addition to the University of Bonn and the University Hospital Bonn, the study involved Children’s Mercy Hospital (USA), the Medical University of Silesia (Poland), the University of Zielona Góra (Poland), the University of Southern Denmark (Denmark), the University of Cologne, the University of Heidelberg, the University of Erlangen-Nuremberg, the Hospital Medeor Lodz (Poland) and the Goethe University of Frankfurt. The work was supported by the German Research Foundation (DFG), the BONFOR program of the University Hospital Bonn, the Else Kröner-Fresenius Foundation, the Luise and Horst Köhler Foundation, and the National Institutes of Health (USA).
Kolvenbach, C.M. et al. (2022) X-linked variations in SHROOM4 are implicated in congenital abnormalities of the urinary tract, anorectal, cardiovascular, and central nervous system. medical genetics journal. doi.org/10.1136/jmg-2022-108738.