On Apr. 3, 2025, a team led by researchers at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital announced reesearch that has deepened our understanding of two other members of the CDKL family, CDKL2 and CDKL1.

The labs of Drs. Oguz Kanca and Hugo Bellen show that variants in these genes can lead to neurodevelopmental conditions, including epilepsy. The team also proposes a mechanism by which the defective variants may cause the neurological symptoms in affected individuals. The study appeared in the American Journal of Human Genetics.

The team discovered that the fruit fly equivalent of human CDKL genes, named Cdkl, is expressed in peripheral sensory neurons, those that perceive sensations like heat, sound and touch, and these neurons project into specific regions in the central nervous system that control sensory inputs.

Deleting the Cdkl gene was lethal to 90% of the flies. The survivors had difficulty climbing – a test of motor function – lost their hearing and had heat-induced seizures and shorter lives. All these consequences were prevented when the normal CDKL1, CDKL2 or CDKL5 human genes were expressed in flies lacking Cdkl, showing that the human and the fly genes work in similar ways and supporting that fruit flies can help understand the human disease better.

In contrast, the CDKL1 and CDKL2 variants the researchers identified in patients only partially rescued the neurological problems observed in the flies lacking Cdkl, indicating that these mutations disrupt the normal function of the gene. “Importantly, expressing CDKL1 or CDKL2 patient variants together with normal CDKL1, CDKL2 or CDKL5 in the flies, suppressed the ability of the normal genes to restore the flies’ sensory problems to normal,” said first author Dr. Ali H. Bereshneh, a postdoctoral fellow in the Kanca and the Bellen labs.