CDKL5 deficiency disorder: molecular insights and mechanisms of pathogenicity to fast-track therapeutic development

Author:

Van Bergen Nicole J.12ORCID,Massey Sean1,Quigley Anita34567ORCID,Rollo Ben8,Harris Alexander R.7,Kapsa Robert M.I.3456,Christodoulou John12910

Affiliation:

1. 1Brain and Mitochondrial Research Group, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia

2. 2Department of Paediatrics, University of Melbourne, Melbourne, Australia

3. 3Electrical and Biomedical Engineering, School of Engineering, RMIT University, Melbourne, VIC, Australia

4. 4Aikenhead Centre for Medical Discovery, St Vincent's Hospital Melbourne, Fitzroy, Melbourne, VIC 3065, Australia

5. 5Centre for Clinical Neurosciences and Neurological Research, St. Vincent's Hospital Melbourne, Fitzroy, VIC 3065, Australia

6. 6Department of Medicine, St Vincent's Hospital Melbourne, The University of Melbourne, Fitzroy, Melbourne, VIC 3065, Australia

7. 7Aikenhead Centre for Medical Discovery, Department of Biomedical Engineering, University of Melbourne, Melbourne 3010, Australia

8. 8Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia

9. 9Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia

10. 10Discipline of Child and Adolescent Health, University of Sydney, Sydney, Australia

Abstract

CDKL5 deficiency disorder (CDD) is an X-linked brain disorder of young children and is caused by pathogenic variants in the cyclin-dependent kinase-like 5 (CDKL5) gene. Individuals with CDD suffer infantile onset, drug-resistant seizures, severe neurodevelopmental impairment and profound lifelong disability. The CDKL5 protein is a kinase that regulates key phosphorylation events vital to the development of the complex neuronal network of the brain. Pathogenic variants identified in patients may either result in loss of CDKL5 catalytic activity or are hypomorphic leading to partial loss of function. Whilst the progressive nature of CDD provides an excellent opportunity for disease intervention, we cannot develop effective therapeutics without in-depth knowledge of CDKL5 function in human neurons. In this mini review, we summarize new findings on the function of CDKL5. These include CDKL5 phosphorylation targets and the consequence of disruptions on signaling pathways in the human brain. This new knowledge of CDKL5 biology may be leveraged to advance targeted drug discovery and rapid development of treatments for CDD. Continued development of effective humanized models will further propel our understanding of CDD biology and may permit the development and testing of therapies that will significantly alter CDD disease trajectory in young children.

Publisher

Portland Press Ltd.

Subject

Biochemistry

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