Rett Syndrome (RTT) is an X-linked neurological disorder and represents the second cause of mental retardation in females. Mutations in the methyl-CpG binding protein (MeCP2) gene cause the majority of RTT cases. Recently, mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene have been found in some RTT patients with the Hanefeld variant. Pathogenic mutations in CDKL5 were also found in females with early signs of developmental delay and epileptic seizure onset, further reinforcing the importance of this gene in mental retardation and epilepsy. We are characterizing the role of CDKL5 in the nervous system thereby clarifying the molecular mechanisms involved in disease onset. We have previously shown that CDKL5 and MeCP2 function in a common pathway; in fact, they associate and the kinase is able to mediate the phosphorylation of MeCP2. This suggests that CDKL5 might also play an indirect role in RTT acting as a modifier gene that, by regulating MeCP2 functions, is able to influence disease severity in patients with mutations in MeCP2. Here we will show that both CDKL5 expression and its subcellular localization are highly modulated during embryogenesis and post-natal development. In addition, in adult mouse, CDKL5 protein level and its cytoplasmic/nuclear fraction are tightly regulated in the different brain areas. Moreover, we will present data demonstrating that CDKL5 shuttles between the nucleus and the cytoplasm and that an active nuclear export mechanism is involved in regulating its localization. Our analysis suggests that the C-terminal tail of the kinase is responsible for the cytoplasmic localization. Importantly, we will show that a number of RTT truncating mutations, found in this region, are mislocalized in the nucleus. We believe that this analysis will contribute in drawing a phenotype-genotype correlation in patients with mutations in CDKL5 and in understanding the role of CDKL5 as an MeCP2 modifier gene.
Molecular characterization of CDKL5, a novel kinase involved in Rett syndrome and infantile spasms
GIUDICI, LAURA;RUSCONI, LAURA;LANDSBERGER, NICOLETTA;KILSTRUP-NIELSEN, CHARLOTTE
2008-01-01
Abstract
Rett Syndrome (RTT) is an X-linked neurological disorder and represents the second cause of mental retardation in females. Mutations in the methyl-CpG binding protein (MeCP2) gene cause the majority of RTT cases. Recently, mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene have been found in some RTT patients with the Hanefeld variant. Pathogenic mutations in CDKL5 were also found in females with early signs of developmental delay and epileptic seizure onset, further reinforcing the importance of this gene in mental retardation and epilepsy. We are characterizing the role of CDKL5 in the nervous system thereby clarifying the molecular mechanisms involved in disease onset. We have previously shown that CDKL5 and MeCP2 function in a common pathway; in fact, they associate and the kinase is able to mediate the phosphorylation of MeCP2. This suggests that CDKL5 might also play an indirect role in RTT acting as a modifier gene that, by regulating MeCP2 functions, is able to influence disease severity in patients with mutations in MeCP2. Here we will show that both CDKL5 expression and its subcellular localization are highly modulated during embryogenesis and post-natal development. In addition, in adult mouse, CDKL5 protein level and its cytoplasmic/nuclear fraction are tightly regulated in the different brain areas. Moreover, we will present data demonstrating that CDKL5 shuttles between the nucleus and the cytoplasm and that an active nuclear export mechanism is involved in regulating its localization. Our analysis suggests that the C-terminal tail of the kinase is responsible for the cytoplasmic localization. Importantly, we will show that a number of RTT truncating mutations, found in this region, are mislocalized in the nucleus. We believe that this analysis will contribute in drawing a phenotype-genotype correlation in patients with mutations in CDKL5 and in understanding the role of CDKL5 as an MeCP2 modifier gene.
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