Recent research has provided significant insights into the Cyclin-dependent kinase-like (CDKL) family of genes, particularly CDKL1 and CDKL2, expanding the understanding of their role in neurodevelopmental disorders. While CDKL5 has been extensively studied for its association with seizures and developmental disorders, the function of other CDKL members has remained largely unexplored. A recent study led by Bereshneh and colleagues sheds light on the involvement of CDKL1 and CDKL2 in conditions such as epilepsy, global developmental delay, and intellectual disability.
The research team identified four novel variants of the CDKL2 gene in five individuals presenting with neurological symptoms, including childhood-onset epilepsy, speech deficits, and intellectual disabilities. Additionally, two previously unreported variants of CDKL1 were linked to developmental disorders through the Developmental Disorders Database (DDD) and GeneDx cohorts. These findings mark a crucial step in understanding how these genes contribute to human health and disease.
CDKL genes are evolutionarily conserved across species, including fruit flies, worms, and mice, making them suitable models for studying gene function. The fruit fly equivalent of human CDKL genes was found to be primarily expressed in peripheral sensory neurons, which are responsible for detecting environmental stimuli such as heat, sound, and touch. Surprisingly, very few neurons in the central nervous system expressed CDKL, despite the association of seizures with central nervous system dysfunctions. This raises important questions about how CDKL mutations affect sensory neurons and contribute to neurological problems.
When researchers deleted the CDKL gene in fruit flies, 90% of them did not survive, while the remaining 10% exhibited severe motor impairments, including climbing difficulties, hearing loss, heat-induced seizures, and reduced lifespan. However, introducing normal human CDKL1, CDKL2, or CDKL5 genes into the flies fully prevented these neurological deficits, demonstrating their functional conservation across species. This underscores the potential of fruit fly models in understanding human neurodevelopmental disorders caused by CDKL mutations.
Further investigations revealed that the newly identified CDKL1 and CDKL2 variants in patients only partially rescued the neurological symptoms in flies lacking CDKL. This suggests that these mutations impair normal gene function. Additionally, when patient-derived variants of CDKL1 or CDKL2 were co-expressed with normal versions of CDKL1, CDKL2, or CDKL5 in fruit flies, they suppressed the corrective effects of the normal genes. This suggests that disease-associated variants exert a dominant-negative effect, meaning that mutated genes interfere with the function of normal genes, thereby contributing to neurological symptoms.
CDKL1 is highly expressed in brain regions associated with cognition, and mutations in this gene may disrupt neuronal growth and signaling pathways essential for learning and memory. Similarly, CDKL2 is involved in neuronal migration, axon guidance, and synaptic function, with pathogenic variants linked to autism spectrum disorder, speech delays, and motor impairments. Researchers suggest that disruptions in CDKL1 and CDKL2 may affect the MAPK/ERK signaling pathway and synaptic protein interactions, potentially leading to deficits in neuronal connectivity. Given their importance, further research is needed to establish genotype-phenotype correlations and explore potential therapeutic strategies.
A previous study by Gomi et al. also found that CDKL2 is highly expressed in brain regions crucial for learning and memory. Mice lacking CDKL2 showed cognitive impairments, reinforcing the role of CDKL genes in neurodevelopmental and neuropsychiatric disorders. The study by Bereshneh and colleagues highlights the role of CDKL1 and CDKL2 in neurodevelopmental disorders and epilepsy, alongside CDKL5. It identifies dominant-negative effects in disease-linked variants and calls for further research into their molecular mechanisms to develop potential therapeutic strategies. These findings open new avenues for understanding and potentially treating neurodevelopmental disorders associated with CDKL gene mutations.
References
- Bereshneh AH, Andrews JC, Eberl DF, Bademci G, Borja NA, Bivona S, et al. De novo variants in CDKL1 and CDKL2 are associated with neurodevelopmental symptoms. The American Journal of Human Genetics [Internet]. 2025 Mar 14 [cited 2025 Mar 17];0(0). Available from: https://www.cell.com/ajhg/abstract/S0002-9297(25)00066-7
- Gomi H, Sassa T, Thompson RF, Itohara S. Involvement of Cyclin-Dependent Kinase-Like 2 in Cognitive Function Required for Contextual and Spatial Learning in Mice. Front Behav Neurosci. 2010 Apr 19;4:17.