CRNKL1 Gene Identified as Key to Rare Neurological Disorder

Ōtākou Whakaihu Waka has led international research that uncovered a new genetic explanation for a rare developmental disorder. This condition has a significant impact on children's brain development and function.

The findings, recently published in the renowned American Journal of Human Genetics, identify specific alterations in a gene known as CRNKL1.

Co-author Associate Professor Louise Bicknell, from the Rare Disorder Genetics Laboratory in Otago’s Department of Biochemistry, stated that this discovery offers new insight into the complex process by which the human body creates the “instruction manuals” needed for brain development and maintenance.

Our bodies rely on a precise process called ‘splicing’ to read and process genetic instructions from our DNA and help generate the building blocks required in our body. While it is known that problems with the machinery that coordinates splicing can cause various genetic disorders, this new finding adds to a small but growing recognition of the potential severe impact on brain development, in particular.

Louise Bicknell, Study Co-author and Associate Professor, University of Otago

The research team studied 10 families affected by a severe genetic disorder. The condition is marked by pre- and post-natal microcephaly (reduced head size), pontocerebellar hypoplasia (underdevelopment of the brainstem and cerebellum), seizures, and significant intellectual disability.

Our journey to this discovery began here in New Zealand, through trying to help New Zealand families get answers for genetic disorders affecting 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.

Louise Bicknell, Study Co-author and Associate Professor, University of Otago

Nine of the families studied showed genetic alterations in the same specific region of the CRNKL1 gene.

All affected children had similar severe symptoms. This highlights a strong link between the genetic changes and the disorder.

Lead author Dr. Sankalita Ray Das, a Postdoctoral Fellow in the Rare Disorder Genetics Laboratory, stated that the findings clearly show CRNKL1 is important for healthy brain development.

Ray Das said, “It also adds to a growing understanding that specific components of the splicing machinery have highly specialized roles, far more intricate than we previously thought.”

She also noted that the discovery not only identifies a new genetic cause for a serious neurological disorder, but also helps explain more about how human genes influence brain development.

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.

Dr. Sankalita Ray Das, Study Lead Author and Postdoctoral Fellow, University of Otago