Human Molecular Genetics Advance Access originally published online on December 5, 2005
Human Molecular Genetics 2005 14(24):3775-3786; doi:10.1093/hmg/ddi391
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
CDKL5/Stk9 kinase inactivation is associated with neuronal developmental disorders
1Department of Neurobiology, Pharmacology and Physiology and 2Ben May Institute for Cancer Research, University of Chicago, Chicago, IL 60637, USA, 3Telethon Institute of Genetics and Medicine, Naples, Italy and 4Medical Genetics, Department of Pediatrics, Federico II University, Naples, Italy
* To whom correspondence should be addressed at: Ben May Institute for Cancer Research, Center for Integrative Sciences (CIS), University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA. Email: m-rosner{at}uchicago.edu
Received September 9, 2005; Accepted October 14, 2005
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.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Ricciardi, C. Kilstrup-Nielsen, T. Bienvenu, A. Jacquette, N. Landsberger, and V. Broccoli CDKL5 influences RNA splicing activity by its association to the nuclear speckle molecular machinery Hum. Mol. Genet., December 1, 2009; 18(23): 4590 - 4602. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Rusconi, L. Salvatoni, L. Giudici, I. Bertani, C. Kilstrup-Nielsen, V. Broccoli, and N. Landsberger CDKL5 Expression Is Modulated during Neuronal Development and Its Subcellular Distribution Is Tightly Regulated by the C-terminal Tail J. Biol. Chem., October 31, 2008; 283(44): 30101 - 30111. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H Rosas-Vargas, N Bahi-Buisson, C Philippe, J Nectoux, B Girard, M A N'Guyen Morel, C Gitiaux, L Lazaro, S Odent, P Jonveaux, et al. Impairment of CDKL5 nuclear localisation as a cause for severe infantile encephalopathy J. Med. Genet., March 1, 2008; 45(3): 172 - 178. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Bertani, L. Rusconi, F. Bolognese, G. Forlani, B. Conca, L. De Monte, G. Badaracco, N. Landsberger, and C. Kilstrup-Nielsen Functional Consequences of Mutations in CDKL5, an X-linked Gene Involved in Infantile Spasms and Mental Retardation J. Biol. Chem., October 20, 2006; 281(42): 32048 - 32056. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H L Archer, J Evans, S Edwards, J Colley, R Newbury-Ecob, F O'Callaghan, M Huyton, M O'Regan, J Tolmie, J Sampson, et al. CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients J. Med. Genet., September 1, 2006; 43(9): 729 - 734. [Abstract] [Full Text] [PDF]
|
|