Healthcare (Commonwealth Union) – The University of Otago has spearheaded global research revealing a novel genetic factor behind a rare developmental condition that significantly affects children’s brain development and cognitive abilities.
The results, newly featured in the esteemed American Journal of Human Genetics, identify precise alterations in the CRNKL1 gene.
Associate Professor Louise Bicknell, a co-author of the study and researcher at the Rare Disorder Genetics Laboratory in the University of Otago’s Department of Biochemistry, stated that the discovery offers new insight into the intricate process the human body uses to generate the instructions necessary for brain development and maintenance.
She pointed out that this process, known as splicing, allows cells to accurately read and interpret genetic information from DNA in order to produce the essential components the body requires. While it is already known that malfunctions in the splicing system can bring about genetic disorders, Bicknell noted that the new research highlights a growing body of evidence connecting these disruptions specifically to severe brain development issues.
Splicing is a key area of gene expression, the process by which information from a gene is utilized to create proteins. While genes are kept as long strands of DNA, they are initially transcribed into RNA, a kind of working copy. However, this raw RNA isn’t ready for use. It contains both useful coding regions, called exons, as well as non-coding regions known as introns.
Before the RNA can bring about the production of proteins, the body must take off the introns and stitch together the exons — a task carried out by a sophisticated molecular machine known as the spliceosome. This editing process, known as RNA splicing, makes sure that the final message sent to the cell’s protein-making factories is precise and functional.
The scientists investigated 10 families affected by a rare and serious genetic condition that causes individuals to develop significant microcephaly both before and after birth (characterised by a smaller head size), along with pontocerebellar hypoplasia (an underdeveloped brain stem and cerebellum), frequent seizures, and profound intellectual impairment.
Associate Professor Bicknell indicated that their path to this breakthrough started right in New Zealand, driven by their efforts to support local families seeking answers about the genetic conditions impacting their children.
“Then, using our international connections, we were able to identify other families around the world, which was crucial for confirming our findings and understanding the full impact of these genetic changes.”
In a major finding, researchers identified that 9 of the families had genetic changes at the exact point within the CRNKL1 gene.
All the children who were impacted displayed the same severe symptoms, underscoring a powerful link between these precise genetic mutations and the condition.
Lead researcher Dr. Sankalita Ray Das, a Postdoctoral Fellow at the Rare Disorder Genetics Laboratory, emphasizes that their study highlights the essential role of the CRNKL1 gene in proper brain development.
She indicated that this discovery deepens their appreciation for how certain components of the splicing machinery carry out highly specialized and unexpectedly complex functions.
According to Dr. Ray Das, the findings not only uncover a previously unknown genetic trigger for a serious neurological condition but also provide valuable insights into the intricate genetic processes that shape brain formation.
“Importantly, this knowledge has provided understanding for families affected by these severe conditions and lays the foundation for further research into why just the brain is affected by these genetic changes.”
By identifying the specific gene responsible for a particular condition, researchers have the possibility of using various technologies such as gene editing or gene silencing, however the treatment will require rigorous testing to be available as a treatment.
The study was backed by funds from the Neurological Foundation of New Zealand, Cure Kids, and the University of Otago.
