Genes play an important role in fetal development

An international study led by the University of Bonn’s Faculty of Medicine has identified a gene that plays a key role in human fetal development. Changes in this can lead to malformations in various organ systems. This gene appeared very early in evolution. It is also present in zebrafish, for example, where it serves a similar function. The result is now Journal of Medical Genetics.

Researchers identified the gene while studying two people with congenital malformations. “It was a man and his niece,” explains Dr. Gabriel Dvorshak. “Both had malformations in their kidneys, urinary tract and esophagus, and the man also had malformations in his right arm and heart.”

Doctors at the University Children’s Hospital in Bonn conduct research into rare genetic diseases at the Institute of Anatomy and Human Genetics. When the research team examined the family’s genetic makeup, they noticed an abnormality. Compared to healthy people, affected people had changes in a gene called SHROOM4.

SHROOM4 was already well known from another context and was known to play an important role in brain function. Mutations can cause intellectual disability, epileptic seizures, and behavioral abnormalities. “However, our findings showed that it may play a broader role in embryonic organ development,” Dvorshak explains.

Bonn’s team successfully investigated other cases internationally where abnormalities in the SHROOM4 gene were found. “Together with our collaborative partners, we were able to identify four more affected individuals from three families,” says Professor Heiko. Mr. Reuter was subsequently transferred from Bonn University Hospital to the University of Erlangen-Nuremberg. “They all had the SHROOM4 gene modified, but not always in the same way.”

Zebrafish also need SHROOM4

However, this did not necessarily reveal whether SHROOM4 variants were actually responsible for the malformations. However, there is an animal with very similar genes, the zebrafish. Currently, it serves as a model organism in many genetic studies. This is not only because they are easy to raise in a species-appropriate manner and can be quickly bred. The skin of the larva is almost transparent. This makes it easy to observe the development of animal embryos under a light microscope. “Here at the University Hospital, we have the advantage that the research group led by Professor Benjamin Odermatt of the Institute of Neuroanatomy studies zebrafish extensively,” emphasizes Dr. Caroline Kolbenbach, who was also involved in the SHROOM4 research. . . “This expertise was helpful in our research.”

The researchers almost completely inactivated SHROOM4 in the larvae. The animals then showed deformities similar to those seen in the patients. On the other hand, when larvae with SHROOM4 switched off were injected with intact human genetic material, they developed almost normally. “This shows, first, that a functional SHROOM4 is absolutely necessary for healthy fish development, and second, that human genes can still take over the function of fish genes.” emphasizes Dvorshak.

The research team now wants to understand what role the gene plays in embryonic development. “We think it’s required for very fundamental processes within cells,” Dvorshak says. “It’s difficult to explain otherwise why changes in the same gene can cause such a wide variety of symptoms.”

A small piece of a very intricate pictorial mosaic

How mice, dogs, and humans develop from fertilized eggs is still not fully understood. This is because eggs have the ability to form all types of tissues in living organisms, including bones, skin, muscles, and the brain. Its daughter cells are genetically identical to it. So in principle you should be able to do the same thing. However, at very early stages, specific programs are activated within cells that determine their developmental fate.

This process requires fine-tuning. Only then can it be ensured that the eyes form in the right places on the face, and at the same time that other cells in close proximity differentiate into nasal cartilage. However, surprisingly, there was no conductor waving his baton. It’s as if Lego spaceships are being assembled automatically, only infinitely more complex. “Our research is a small part of this picture mosaic, and it’s still largely incomplete,” Dvorshak says.

Participating institutions and funding:

In addition to the University of Bonn and Bonn University Hospital, the research included Children’s Mercy Hospital (USA), Medical University of Silesia (Poland), University of Zielona Góra (Poland), University of Southern Denmark (Denmark), University of Cologne, and University of Heidelberg. , University of Erlangen-Nuremberg, Lodz Medeor Hospital (Poland), and Goethe University Frankfurt. This study was supported by the German Research Foundation (DFG), her BONFOR program at Bonn University Hospital, the Else Kroner-Fresenius Foundation, the Luise and Horst Köhler Foundation, and the National Institutes of Health (USA).

Publication: Caroline M. Kolvenbach et al.: X-linked mutations in SHROOM4 are associated with birth defects of the urinary tract, anorectal, cardiovascular, and central nervous system. Journal of Medical Genetics; DOI: 10.1136/jmg-2022-108738

contact:

Dr. Gabriel Dvorshak
Bonn University Children’s Hospital
Institute of Anatomy and Human Genetics
Phone: +49 228 739033
Email: gabriel.dworschak@uni-bonn.de