CDKL5

Cyclin-dependent kinase-like 5 (CDKL5) is a serine/threonine protein kinase that in humans is encoded by the ''CDKL5'' gene. It is critically involved in early brain development and function, particularly in neuronal maturation and synaptic regulation. Mutations in ''CDKL5'' are associated with CDKL5 deficiency disorder (CDD), a severe neurodevelopmental condition that manifests with early-onset epilepsy, developmental delay, and motor and cognitive impairment. CDKL5 is closely related to the cyclin-dependent kinase family and has been implicated in disorders such as Rett syndrome and other epileptic encephalopathies.

Gene

The ''CDKL5'' gene is located on the X chromosome at locus Xp22. It undergoes alternative splicing to produce multiple transcript variants. Pathogenic variants in ''CDKL5'' can result in either loss of function or altered subcellular localization of the protein, which contributes to disease pathology. The gene is expressed predominantly in the brain and is particularly active during early developmental stages.

Structure

CDKL5 encodes a serine/threonine kinase with a highly conserved catalytic domain similar to cyclin-dependent kinases (CDKs), though it functions independently of cyclins. The C-terminal region of the protein plays a critical role in its subcellular localization and regulation. During neuronal development, CDKL5 localizes to both the nucleus and cytoplasm, with nuclear localization being essential for its role in gene regulation and splicing.

Function

CDKL5 plays a central role in neuronal function by regulating signal transduction pathways that influence dendritic spine morphology, synaptogenesis, and neuronal survival. It is involved in the phosphorylation of target proteins that modulate neuronal activity and gene expression. CDKL5 has also been shown to interact with nuclear speckles and influence RNA splicing machinery, which may underlie some of its neurodevelopmental functions.

Clinical significance

Mutations in ''CDKL5'' cause CDKL5 deficiency disorder (CDD), an X-linked dominant condition characterized by early-onset epileptic seizures, severe intellectual disability, and motor dysfunction. CDD is considered distinct from classic Rett syndrome, although overlapping features have been noted, especially in female patients. Clinical presentations of ''CDKL5'' mutations can vary widely, and cases have been reported in both males and females. Genetic testing for ''CDKL5'' is recommended in infants presenting with epileptic encephalopathy of unknown origin. Research is ongoing into potential therapies, including gene therapy and molecular modulation of downstream targets.

See also

* Cyclin-dependent kinase
* Rett syndrome
* West syndrome
* CDKL5 deficiency disorder

References

Further reading

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External links

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Cure CDKL5 Disorder
resources for Families and Professionals - based in the UK

International Foundation for CDKL5 Research
- based in the US

CDKL5 Forum
- a professional forum to share current research on CDKL5 and to stimulate peer-group discussion

CDKL5 Foundation Netherlands
- CDKL5 Foundation based in holland for research, information and collaboration

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