SHROOM4 Gene Plays Essential Role in Embryonic Development

Researchers from the University of Bonn recently identified a gene that plays an essential role in the development of human embryos. The gene, SHROOM4, was previously identified to play a role in brain function, but the scientists uncovered its additional roles in development in their paper, published in the Journal of Medical Genetics.

Their work began when physicians at the University Children's Hospital in Bonn conducted research on rare genetic diseases at the Institutes of Anatomy and Human Genetics. "It was a man and his niece," explains senior author Dr. Gabriel Dworschak. "Both had malformed kidneys, urinary tract and esophagus, and the man also had a malformed right arm and heart." When the team examined the genetic profiles of these two individuals, they discovered that SHROOM4 was altered in affected individuals compared to healthy individuals. 

To corroborate these findings, the team searched internally for other cases where mutations in SHROOM4 had also been identified. "Together with our cooperation partners, this led us to four more affected individuals from three families," says Prof. Dr. Heiko Reutter, who has since moved from the University Hospital Bonn to the University of Erlangen-Nuremberg. "All of them had the SHROOM4 gene altered, but not always in the same way."

However, these discoveries did not necessarily clarify whether SHROOM4 variants were directly related to these malformations. For further assessment, the team utilized an animal with a similar gene – zebrafish.

Since embryos for this model organism are translucent, it made it easy for the researchers to study their development under a light microscope. "Here at the University Hospital, we have the advantage that the research group led by Prof. Dr. Benjamin Odermatt from the Institute of Neuroanatomy works a lot with zebrafish," stresses first author Dr. Caroline Kolvenbach. "This expertise came in handy in our study."

The team inactivated SHROOM4 in zebrafish larvae and observed similar malformations like those observed in human patients. To verify these findings, they also injected intact human genetic material into larvae with SHROOM4 switched off and observed healthy development for those fish. "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," Dworschak emphasizes.

For future work, the team wants to find out which part of the gene plays a role 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 such a variety of symptoms."

While embryonic development is still a complicated and elusive process, findings like these help create the bigger picture. "Our study is a small piece of the mosaic to this picture, which is still largely incomplete," says Dworschak.