Rett syndrome (RTT) is a disorder that affects approximately 1 in every 10,000 to 15,000 live female births and is one of the leading causes of mental retardation and autistic features in females. Most patients survive into middle and old age, in a very disabled condition. Misdiagnosis of RTT individuals as autistic is not uncommon, since there is significant overlap in clinical features between these two conditions, including impaired language, stereotypic behaviors, frequent seizures, sleep disturbances and the onset of symptoms after a period of apparently normal development. Indeed, both disorders are considered as pervasive developmental disorders (PDD). RTT is caused by mutations in MECP2, located in the X chromosome and encoding for MeCP2, a nuclear protein that binds to methylated CpGs and regulates gene expression. Notably, it has been shown that the RTT-like phenotype exhibited by a Mecp2 null mouse model of the disease could be fully reversed by post-symptomatic activation of MeCP2. These data provide hope for phenotypic amelioration in some cases of RTT. However, the majority of RTT cases is caused by missense and nonsense mutations of MeCP2 rather than by deletions or other type of null mutations. Since only one allele of MeCP2 is expressed in a given cell (due to X chromosome inactivation or hemizygosity), these non- null mutant versions of MeCP2 cannot have autologous dominant negative activities. However, the possibility of mutant versions of MeCP2 exerting dominant negative effects upon purposefully expressed wild type MeCP2 cannot be excluded so far. We here propose to use non-null mouse models of RTT to determine the phenotypic response of transgenic restoration of MeCP2. This is a relevant task that will contribute to the design of future therapeutic interventions. Our accumulated experience in the study of MeCP2 mouse models and the possession of transgenic mice expressing versions of MeCP2 capable of compensate the lack of endogenous MeCP2 put us in a unique position to complete the proposed research. We plan to compare the ability of exogenous MeCP2 to prevent the development of RTT-like phenotypes in Mecp2 null versus non-null mouse models of RTT.
We will use mouse and cellular models of Rett syndrome to test whether the effect of mutations that affect MeCP2's functionality (but do not eliminate the protein) could be reversed by transgenic restoration of MeCP2. This is a relevant task that will contribute to the design of future therapeutic interventions. Our accumulated experience in the study of MeCP2 mouse models, the availability of experienced collaborators and the possession of transgenic mice expressing versions of MeCP2 capable of compensate the lack of endogenous MeCP2 put us in a unique position to complete the proposed research.
