New members of the CDKL family of genes linked to neurodevelopmental disorders

(Press-News.org) CDKL5, one of the five members of the CDKL family of genes, is important for proper neurodevelopment and associated with seizures. However, the role the other four members of this family play in health and disease is unknown.

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 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.

“CDKL5 was until now the only gene of the CDKL family linked to neurodevelopmental disorders in people,” said first author Dr. Ali H. Bereshneh, a postdoctoral fellow in the Kanca and the Bellen labs. “Here we report four new variants of CDKL2 identified in five individuals presenting with overlapping symptoms, including global developmental delay, intellectual disability, childhood-onset epilepsy and speech deficits.”

In addition, the researchers identified two new variants of CDKL1 in the published Deciphering Developmental Disorders (DDD) and GeneDx cohorts associated with developmental disorders.

CDKL genes are highly conserved – they also are present in animals like fruit flies, worms and mice – which enables researchers to work with these animal models as ‘living test tubes’ to better understand how CDKL genes cause neurodevelopmental conditions.

“We worked with the laboratory fruit fly, an animal model very well suited and studied to investigate how genes work,” said Kanca and Bellen, corresponding authors of the work. Kanca is an assistant professor of molecular and human genetics at Baylor and the Duncan NRI. Bellen is the Distinguished Service Professor of molecular and human genetics at Baylor and chair in neurogenetics in the Duncan NRI.

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.

“In contrast, very few neurons in the central nervous system itself expressed Cdkl,” Kanca said. “This was a surprise because generally seizures are associated with central nervous system dysfunctions. We want to understand how the Cdkl mutations change the sensory neurons and cause seizures and other neurological problems.”

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. Hence, working with the fruit fly model 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,” Bereshneh said.

“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,” Kanca said. “Further studies will help elucidate the precise mechanisms mediating the negative effect of these mutations.”

Jonathan C. Andrews, Daniel F. Eberl, Guney Bademci, Nicholas A. Borja, Stephanie Bivona, Undiagnosed Diseases Network, Baylor College of Medicine Center for Precision Medicine Models, Wendy K. Chung, Shinya Yamamoto, Michael F. Wangler, Shane McKee and Mustafa Tekin also are contributors to this work. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, University of Iowa, University of Miami Miller School of Medicine, Harvard Medical School and Belfast City Hospital.

This work was supported by the Huffington Foundation, the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Southern Star Medical Research Institute, the Office of Research Infrastructure Programs of the National Institutes of Health (grants R24OD031447, U54OD030165, R24OD022005, U54OD030165, U54NS093793, U2CNS132415-01S01) and the National Science Foundation (grant 2037828).

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