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Human Molecular Genetics Advance Access published online on December 5, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi391
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© The Author 2005. Published by Oxford University Press. All rights reserved The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oupjournals.org
Received September 9, 2005
Revised October 14, 2005
Accepted October 14, 2005

Article

CDKL5/Stk9 Kinase Inactivation is Associated with Neuronal Developmental Disorders

Clark Lin 1, Brunella Franco 2, and Marsha Rich Rosner 1 *

1 Department of Neurobiology, Pharmacology and Physiology, University of Chicago, Chicago, IL 60637; Ben May Institute for Cancer Research, Center for Integrative Sciences (CIS), University of Chicago, 929 East 57th Street, Chicago, IL 60637
2 Telethon Institute of Genetics and Medicine, Naples, Italy; Medical Genetics, Department of Pediatrics, Federico II University, Naples, Italy

* To whom correspondence should be addressed.
Marsha Rich Rosner, E-mail: m-rosner{at}uchicago.edu


  Abstract

X-linked cyclin-dependent kinase-like 5 (CDKL5 or STK9) has recently been implicated in atypical Rett and X-linked West Syndromes, severe neurological disorders associated with mental retardation, loss of communication and motor skills, and infantile spasms and seizures in predominantly females. Besides CDKL5 these disease phenotypes are also linked to mutations in the MECP2 and ARX genes. Here, we have expressed and characterized CDKL5 and its mutant forms. CDKL5 is a 118 kDa protein that is widely distributed in all tissues, with highest levels in brain, thymus, and testes. Whole mount embryo staining reveals CDKL5 to be ubiquitous. Within cells, CDKL5 is localized primarily in the nucleus. Removal of the C-terminal domain increases CDKL5 expression, enhances autophosphorylation activity, and causes perinuclear localization, indicating that the C-terminus regulates CDKL5 function. Although we detect MeCP2 but not ARX binding to CDKL5, our results suggest that neither of these proteins are direct substrates of the CDKL5 kinase. Finally, the CDKL5 mutations associated with the disease phenotype cause loss of kinase activity as assessed by autophosphorylation. These results suggest that inactivation of the CDKL5 kinase can lead to severe neurodevelopmental disorders.

Keywords: CDKL5; Stk9; Serine-threonine kinase; MeCP2; ARX; Rett Syndrome; West Syndrome.
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