Molecular characterization of CDKL5, a novel kinase involved in Rett syndrome and infantile spasms

Rett Syndrome (RTT) is an X-linked neurological disorder affecting mainly females. In the classical form, patients have normal period of development of 6-18 months where after they display developmental arrest and a progressive regression leading to the loss of speech and purposeful movements with the appearance of a severe mental retardation. Atypical forms with differences in disease onset and severity exist. Mutations in the methyl-CpG binding protein (MECP2) gene, located on Xq28, cause the majority of RTT cases but have been found in less than half of atypical RTT patients. Recently, mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene, on Xp22, have been found in some RTT patients with the Hanefeld variant, characterized by the onset of seizures in the very first months of life. Furthermore, mutations in CDKL5 have been found in girls with infantile spasms and mental retardation, suggesting an important role of this gene for neuronal function. A main interest of our laboratory is to characterize the role of CDKL5 in the nervous system thereby clarifying the molecular mechanisms involved in disease onset. With this communication we will present our results showing that CDKL5 and MeCP2 function in a common pathway in accordance with the fact that mutations in the two genes cause a similar phenotype. In fact, besides sharing an overlapping expression pattern correlating with neuronal maturation and synaptogenesis, CDKL5 and MeCP2 associate and in vitro the kinase is able to mediate the phosphorylation of the methyl-binding protein. Furthermore, we will show our unpublished data indicating that CDKL5 catalytic activities are subject to different levels of regulation mediated by its long C-terminal tail. First of all, the C-terminus influences negatively the catalytic activity of the kinase and, moreover, an active nuclear export mediated by the tail is involved in regulating the subcellular localization of CDKL5. Finally, the turn over of the kinase seems to be regulated and disease causing mutations might affect it. It is important to keep in mind that besides missense mutations in the N-terminal catalytic domain a number of truncating mutations are found in the C-terminal tail; with the functional analysis of these mutated derivatives we try to provide a molecular explanation to their contribution to Rett Syndrome. We believe that this analysis will contribute in drawing a phenotype-genotype correlation.