Gene plays major role in brain development

Study by the University of Bonn shows that mutations of the investigated gene manifest in different patterns of inheritance

The so-called Plexin-A1 gene seems to play a more extensive role in brain development than previously assumed. This is shown by a current study led by the University Hospital Bonn and the Institute of Anatomy of the University of Bonn with more than 60 international partners. The gene is also interesting for another reason: Its mutations are inherited either dominantly or recessively, depending on which part of the gene is affected. The results of the study are now published in the journal “Genetics in Medicine”.

When the Augustinian monk Gregor Mendel crossed white-flowering with purple-flowering pea plants in the mid-19th century, he made an interesting discovery: The offspring were all purple. He therefore called this trait dominant, while the white blossom color was recessive. The reason for this phenomenon: In peas, each gene occurs twice. One version comes from the maternal plant and the other from the paternal plant. If a pea has inherited the gene for purple flower color from one parent, but the gene for white flower color from the other, purple wins. Only when two genes for white flowers come together in the offspring plant is it white.

Humans also have genes that are inherited either dominantly or recessively. However, the case is not so clear for the mutations investigated in the study: Some of them are dominant, meaning that a mutation inherited either by the mother or by the father is sufficient for the mutation to have an impact. Others, however, are recessive. “This has also been observed sporadically with other genes, but it was still unexpected,” explains Dr. Gabriel Dworschak, pediatrician at the University Children’s Hospital who conducted his research at the Institute of Anatomy and the Institute of Human Genetics.

The gene came into the focus of the researchers when they examined a girl with severe malformations of the esophagus, brain and eyes at University Hospital Bonn. A genetic analysis revealed that her Plexin-A1 gene was different from that of healthy individuals. “We then searched a database for other affected individuals with mutations in the plexin gene,” explains Prof. Dr. Heiko Reutter, physician at the University Children’s Hospital and staff member at the Institute of Human Genetics at the University of Bonn.

The researchers have now found a total of ten patients in this way; they come from seven families. “The affected individuals all had different parts of the Plexin-A1 gene altered,” Dworschak points out. “Five of these mutations are inherited recessively; the remaining three are dominant.” Further analysis helped the researchers understand why this is the case: The Plexin-A1 gene contains the building instructions for a receptor. It is located in the membrane that surrounds the nerve cells like a thin skin. Certain messenger molecules can dock onto its outer surface. This then triggers a response at the other end of the receptor that protrudes into the cell. […]

Participating Core Facilities: The authors acknowledge the support from the Zebrafish Core Facility.

Participating institutions and funding:
The study involved institutions from the USA, Turkey, India, Saudi Arabia, Pakistan, the United Kingdom, Australia, France, Canada, Italy and Germany. Dr. Jaya Punetha of Baylor College of Medicine in Texas is lead author of the study, together with Dr. Dworschak. The work was supported, among others, by the German Research Foundation (DFG) and by various funding agencies in the participating countries.

Publication: G. C. Dworschak et al.: Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies; Genetics in Medicine; DOI: 10.1038/s41436-021-01196-9

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