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Molecular and genetic insights into an infantile epileptic encephalopathy – CDKL5 disorder

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Frontiers in Biology

Abstract

Background

The discovery that mutations in cyclin-dependent kinase-like 5 (CDKL5) gene are associated with infantile epileptic encephalopathy has stimulated world-wide research effort to understand the molecular and genetic basis of CDKL5 disorder. Given the large number of literature published thus far, this review aims to summarize current genetic studies, draw a consensus on proposed molecular functions, and point to gaps of knowledge in CDKL5 research.

Methods

A systematic review process was conducted using the PubMed search engine focusing on CDKL5 studies in the recent ten years. We analyzed these publications and summarized the findings into four sections: genetic studies, CDKL5 expression patterns, molecular functions, and animal models. We also discussed challenges and future directions in each section.

Results

On the clinical side, CDKL5 disorder is characterized by early onset epileptic seizures, intellectual disability, and stereotypical behaviors. On the research side, a series of molecular and genetic studies in human patients, cell cultures and animal models have established the causality of CDKL5 to the infantile epileptic encephalopathy, and pointed to a key role for CDKL5 in regulating neuronal function in the brain. Mouse models of CDKL5 disorder have also been developed, and notably, manifest behavioral phenotypes, mimicking numerous clinical symptoms of CDKL5 disorder and advancing CDKL5 research to the preclinical stage.

Conclusions

Given what we have learned thus far, future identification of robust, quantitative, and sensitive outcome measures would be the key in animal model studies, particularly in heterozygous females. In the meantime, molecular and cellular studies of CDKL5 should focus on mechanism-based investigation and aim to uncover druggable targets that offer the potential to rescue or ameliorate CDKL5 disorder-related phenotypes.

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Acknowledgements

We thank Sheng Tang for his assistance in organizing the references and Judy I-Ting Wang in formulating the review plan. We also acknowledge the sponsorship from the Sino-US Health Science Initiative (A.Z. and S. H.). This work is partially supported by the International Foundation for CDKL5 Research and the Loulou Foundation.

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Authors and Affiliations

  1. Jiaozhou People’s Hospital, Jiaozhou, Shangdong, 266300, China

    Ailing Zhou & Song Han

  2. Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA

    Zhaolan Joe Zhou

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  1. Ailing Zhou
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  2. Song Han
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Correspondence to Zhaolan Joe Zhou.

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Zhou, A., Han, S. & Zhou, Z.J. Molecular and genetic insights into an infantile epileptic encephalopathy – CDKL5 disorder. Front. Biol. 12, 1–6 (2017). https://doi.org/10.1007/s11515-016-1438-7

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  • DOI: https://doi.org/10.1007/s11515-016-1438-7

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