Researchers at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute have expanded knowledge on the CDKL gene family, particularly CDKL2 and CDKL1. The study, led by Drs. Oguz Kanca and Hugo Bellen, identified variants in these genes linked to neurodevelopmental disorders such as epilepsy. The findings were published in the American Journal of Human Genetics.
Dr. Ali H. Bereshneh, a postdoctoral fellow involved in the research, stated: “CDKL5 was until now the only gene of the CDKL family linked to neurodevelopmental disorders in people.” He reported discovering four new variants of CDKL2 associated with symptoms like developmental delay and childhood-onset epilepsy.
The researchers also found two new variants of CDKL1 related to developmental disorders in existing cohorts. These genes are conserved across species, allowing studies using animal models like fruit flies to understand their role in neurodevelopmental conditions.
Kanca and Bellen explained that experiments with fruit flies showed Cdkl expression primarily in peripheral sensory neurons rather than central nervous system neurons. This was unexpected given seizures' typical association with central nervous system issues.
Deletion of the Cdkl gene proved lethal for most flies, but normal human genes could rescue these effects when expressed in flies lacking Cdkl. However, patient-derived variants only partially mitigated neurological problems, suggesting they disrupt normal gene function.
Bereshneh noted: “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.”
Kanca added: "The results suggest that these disease-associated variants mediate their effects by negatively interfering with the function of the normal genes: they have a dominant negative effect that leads to neurological symptoms in affected individuals."
Contributors to this research include Jonathan C. Andrews, Daniel F. Eberl, Guney Bademci among others from institutions such as Baylor College of Medicine and Harvard Medical School. Funding was provided by several organizations including the Huffington Foundation and National Institutes of Health.
