An international study conducted by the Faculty of Medicine of the University of Bonn has identified a gene that plays an important role in the development of the human embryo. If it is impaired, malformations of various organ systems can result. The gene appeared very early in evolution. It also exists in zebrafish, for example, and performs a similar function there. The results have just been published in the Journal of Medical Genetics.
Researchers found the gene when they studied two people with birth defects.
It was a man and his niece. Both had malformed kidneys, urinary tract and esophagus, and the man also had a malformed right arm and heart.”
Dr. Gabriel Dworschak
The doctor at the Bonn University Children’s Hospital conducts research into rare genetic diseases at the Institutes of Human Anatomy and Genetics. When the team looked at the genetic makeup 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 in another context: it was known to play a key role in brain function. Mutations can lead to intellectual disability, seizures, and behavioral abnormalities. “Our results, however, indicated that it may play a broader role in the development of embryonic organs,” says Dworschak.
The Bonn team searched internationally for other cases in which SHROOM4 gene abnormalities were also found – and succeeded: “Together with our cooperation partners, this has led us to four more affected people from three families,” says Professor Dr Heiko Reutter, who has since moved from the University Hospital Bonn to the University of Erlangen-Nuremberg. “All had the modified SHROOM4 gene, but not always in the same way.”
Zebrafish also need SHROOM4
However, this did not necessarily clarify whether the SHROOM4 variants were actually responsible for the malformations. But there is an animal that has a very similar gene: the zebrafish. It serves today as a model organism in many genetic studies – and not only because it is easy to keep in a species-appropriate way and reproduces quickly: the skin of its larvae is almost transparent. This makes it easier to observe the embryonic development of animals under a light microscope. “Here at the CHU, we have the advantage that the research group led by Pr Dr Benjamin Odermatt of the Institute of Neuroanatomy works a lot with zebrafish”, underlines Dr Caroline Kolvenbach, also involved in the SHROOM4 study. . “This expertise proved useful in our study.”
The researchers almost completely inactivated SHROOM4 in the larvae. The animals then presented malformations similar to those observed in the patients. If, on the other hand, the larvae with SHROOM4 extinguished received the intact human genetic material, they developed almost normally. “This shows firstly that they absolutely need a functioning SHROOM4 for healthy development; and secondly, that the human gene can still support the function of the fish gene,” Dworschak points out.
The team now wants to know what role the gene plays in embryonic development. “We assume it’s needed for very basic processes in the cell,” says Dworschak. “It is difficult to explain otherwise why changes in the same gene cause such a variety of symptoms.”
Small piece in the mosaic of an extremely complex image
How a mouse, dog, or human develops from a fertilized egg is still not fully understood. Indeed, the egg has the ability to form any type of tissue in the body, whether bone, skin, muscle or brain. Its daughter cells are genetically identical to it; therefore, in principle, they should be able to do the same. But at a very early stage, certain programs are activated in their cells which irrevocably determine their developmental fate.
This process must be coordinated down to the smallest detail. Because only then is it ensured that the eyes form in the appropriate place on the face, while other very close cells differentiate in the nasal cartilage. Surprisingly, however, there is no baton-wielding conductor. It’s like a Lego spaceship assembling itself – only infinitely more complicated. “Our study is a small piece of the mosaic of that picture, which is still largely incomplete,” Dworschak said.
Participating Institutions and Funding:
Besides the University of Bonn and University Hospital Bonn, the study involved Children’s Mercy Hospital (USA), Medical University of Silesia (Poland), University of Zielona Góra (Poland) , University of Southern Denmark (Denmark), University of Cologne, University of Heidelberg, University of Erlangen-Nuremberg, Medeor Hospital Lodz (Poland) and Goethe University Frankfurt. The work was supported by the German Research Foundation (DFG), the BONFOR program at the University Hospital Bonn, the Else Kröner-Fresenius Foundation, the Luise and Horst Köhler Foundation and the National Institutes of Health (USA).
Kolvenbach, CM, et al. (2022) X-linked variations of SHROOM4 are implicated in birth defects of the urinary tract, anorectal, cardiovascular, and central nervous system. Journal of Medical Genetics. doi.org/10.1136/jmg-2022-108738.
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