Investigators:
N. Carolyn Schanen, MD, PhD
Background: Rett syndrome and transcriptional silencing Rett syndrome (RTT) is a common cause of mental retardation, affecting 1 in 10-15,000 females worldwide. These patients appear to be normal at birth, then between 6-18 months of age they lose their language, and acquire characteristic hand manipulations and a poorly coordinated gait. A developmental plateau follows the regression; however, by that time they are nonverbal, often non-ambulatory, and appear to be severely mentally retarded. The clinical features of RTT are consistent with a disruption of normal development and maintenance of cortical neuronal systems in the brain. RTT is a genetic disorder that is frequently caused by mutations in the X-linked MECP2 gene. The current model predicts that MECP2 blocks gene expression by binding to DNA that has been modified by methylation on cytosine residues. MECP2 recognizes the modfied DNA and interacts with other proteins that effect chromatin remodeling such as histone deacetylases and the transcriptional corepressor Sin3A. Cytosine methylation is an important mechanism of gene silencing, both in terms of stable silencing of regions DNA that does not encode genes and in the reversible regulation of gene expression. It is used in processes such as X-chromosome inactivation and imprinting, as well as for tissue-specific and developmental regulation of gene expression. Approximately 80% of patients with classical Rett syndrome have mutations in the MECP2 gene. The gene has also now been shown to be involved in other developmental disorders such as Angelman syndrome, mental retardation in boys with neurological symptoms, and autism, as well as mild learning disabilities in some girls.
What We're Doing
We are taking several avenues to explore the role of methylation-dependent transcriptional silencing in neuronal development using both cell culture and model organism-based systems. Because Rett syndrome primarily affects the way the brain develops and functions, we are focusing on the function of the MeCP2 protein in the growth and development of neurons, including the response to growth factors and hormones that regulate development. We are also investigating the ways that the mutations in the gene affect the proteins ability to recognize the DNA targets and interact with the other proteins in the complex.
Some of What We've Found
To understand whether certain types of mutations in MECP2 were associated more with symptom severity, we collaborated with Alan K. Percy, MD (University of Alabama) to perform a large scale study of 85 patients with MECP2 mutations. To do this, we needed to devise a reproducible scale for judging severity of the different clinical features. Using this system, we identified types of mutations that are associated with milder or more severe symptoms in children with classical and atypical Rett syndrome. We have also identified MECP2 mutations in several unusual patients that do not have Rett syndrome, but had either more severe or milder symptoms. Determining the range of severity of the symptoms associated with MECP2 mutations will help physicians better identify patients at early stages of the disorder, allowing them to begin therapies sooner.