Gene's role in embryonic organ development discovered

Malformations in organ development have been found to be caused by mutations of a gene expressed in early embryogenesis.

The gene SHROOM4, has so far been linked to brain function – its mutations have been associated with the neurodevelopmental disorder Stocco dos Santos syndrome, causing intellectual impairment, epileptic seizures, and behavioural abnormalities. However, researchers at the University of Bonn, Germany, have discovered a new role for the gene by studying patients with similar malformations to each other.

Dr Gabriel Dworschak, physician and developmental geneticist at the University of Bonn, and corresponding author of the study, explained: 'It was a man and his niece… Both had malformed kidneys, urinary tract and oesophagus, and the man also had a malformed right arm and heart.'

When the team analysed the genetic makeup of the family members, they found that they shared alterations in the genetic sequence of SHROOM4, leading them to suspect that this was behind their symptoms. The researchers also identified other people from around the world who displayed similar symptoms.

'This led us to four more affected individuals from three families,' said Professor Heiko Reutter of the University of Erlangen-Nuremberg, Germany, and co-author of the study. He continued: 'All of them had the SHROOM4 gene altered, but not always in the same way.'

To study the role of the gene in organ development, the team inactivated the version of SHROOM4 in zebrafish, a common and well-studied model of embryogenesis. The fish subsequently exhibited similar developmental malformations to those seen in human patients.

The mutated zebrafish embryos were then injected with a functional form of the human gene, which mostly reversed the developmental malformations. Not only did this suggest that mutations in SHROOM4 were responsible, but that the gene is fundamental to early development, reaching far back in the evolution of animals.

Dr Dworschak explained: '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… We assume that it is needed for very basic processes in the cell.'

The team, noted in their paper published in the Journal of Medical Genetics, that the gene may regulate the cell's microscopic skeletal structure, and hope to investigate further how it functions to control embryo formation.