Molecular Pathogenic Studies of Rett Syndrome
In 1999, my lab discovered that the postnatal developmental disorder known as Rett syndrome (RTT) is caused by mutations in the X-linked gene MECP2 , which encodes methyl-CpG-binding protein 2 (MeCP2). Female children with classic RTT typically reach early milestones, but around the age of two begin to lose acquired language and motor skills and develop a variety of neurological deficits such as autonomic dysfunction, ataxia, tremors, seizures, autistic features, and stereotypic hand movements. We and others have found that MeCP2 mutations underlie a range of developmental and mental disorders, in both females and males, such as autism, mild mental retardation, and psychosis with motor dysfunction.
Because favorably skewed X-chromosome-inactivation patterns cause only very mild disease in some females, we proposed that the broad phenotype of classic RTT results from MeCP2 dysfunction in particular subsets of neurons. MeCP2 has been shown to be a transcriptional repressor that links DNA methylation to chromatin modifications; our lab has found that MeCP2 also interacts with an RNA-binding protein and can affect RNA splicing. More recently, and more unexpectedly, we have discovered that MeCP2 interacts with CREB to activate , rather than suppress, a number of genes. We thus hypothesized that loss of function of MeCP2 in specific neurons causes changes in gene expression and RNA splicing that mediate the neuron-specific phenotypes.
Our aims are to: (1) identify the neuroanatomical bases of several key features of RTT by deleting Mecp2 in distinct neuronal populations (using Cre/LoxP technology) and characterizing the phenotypes of the conditional mutant mice; (2) identify MeCP2 targets by evaluating neuron-specific gene expression and splicing pattern changes in Mecp2 308/Y mice that reproduce RTT phenotypes (we are using a novel approach that employs neuron-specific BACarray lines and new splicing/expression arrays); (3) conduct preclinical pharmacologic trials targeted at clinically relevant molecular changes (based on Data from Aims 1 and 2) to determine whether such therapies can alter the course of RTT. As a proof of concept, we will use drugs that modulate the activities of CRH and AVP, which we have shown are MeCP2 targets involved in specific RTT phenotypes.
Relevance of the project to IDDRC mission:
Rett syndrome and other MeCP2 disorders are a major cause of cognitive, emotional, and physical disability. These studies are already providing insight into the neuronal subtypes and neurotransmitter systems that mediate certain key features of RTT and related disorders such as autism and X-linked mental retardation. They will provide the community with a rich resource of neuron-specific gene expression/splicing patterns and knowledge of how some of these patterns differ in RTT. Last but not least, the data generated under this study have the potential to identify effective pharmacologic interventions that could benefit RTT patients.