Laboratory of Genetic and Epigenetic Control of Gene Expression Lab Profile

Research Focus: Molecular mechanisms by which MECP2 and CDKL5 mutations cuase Rett syndrome and mental retardation

Although mutations in MECP2 are responsible for the majority of Rett cases, patients without mutations in this gene exist. The number of patients with classic Rett that do not carry mutations in MECP2 is only 5-10%; conversely, this number is much higher (approximately 50%) in patients affected by variant forms of the disease. Another problem concerning RTT is that patients with identical MeCP2 mutations manifest very different symptoms and, furthermore, mutations in this gene have been identified also in patients affected by autism, mental retardation and Angelman Syndrome (http://www.angelman.org/angel/). Altogether, these data suggest that other genes may be involved in causing Rett Syndrome or influencing the disease severity. Accordingly, mutations in the cyclin-dependent kinase like 5 gene, CDKL5, located at Xp22 (OMIM 300203 link), have recently been identified in patients affected by the Hanefeld variant, which is characterized by the early onset of seizures. Later on, CDKL5 has been shown to implicated in cases of mental retardation together with infantile spasms, suggesting that this gene is important for nervous system functions. Experiments from our laboratory show that CDKL5, as expected from its primary structure, is a kinase that shares strong homology to the MAP-kinases and cyclin-dependent kinases. Furthermore, we have shown that CDKL5 and MeCP2 interact and that, in vitro, CDKL5 is able to mediate the phosphorylation of MeCP2.
Our laboratory is working on understanding in more details the molecular mechanisms of how MeCP2 exerts its functions. We consider it important to identify and characterize novel MeCP2-interacting proteins since these may be involved in regulating the activity of MeCP2 in different ways; these factors may be involved in RTT either indirectly by regulating MeCP2 activities or directly. To this end we have utilized biochemical, genetic, and deductive approaches and found some proteins interacting with MeCP2. The present projects in the laboratory are focused on characterizing the functional role of these interactions. Regarding CDKL5, besides characterizing the importance of its interaction with MeCP2 we are also trying to understand the role of CDKL5 for nervous system functions.