Our research focuses on understanding the molecular and cellular basis of human neurogenetic disorders.
Our Work on Rett Syndrome
Rett syndrome (RTT) is a common cause of intellectual disability in females, affecting approximately 1 in 15,000 females worldwide. Though girls with RTT appear to be normal at birth, they then lose their language between 6-18 months of age, and acquire characteristic hand movements with commensurate loss of purposeful hand skills.
A developmental plateau follows the regression; however, by that time they are generally nonverbal, often non-ambulatory and appear have severe intellectual disability although each aspect of the phenotype is quite variable. In addition, patients with RTT are at risk for a number of other health problems including epilepsy, disordered breathing, osteoporosis, and scoliosis.
RTT is a genetic disorder that is frequently caused by mutations in the X-linked MECP2 gene. The encoded protein, MeCP2, is a multidomain, chromatin associated protein that plays a role in transcriptional regulation. There are eight common recurrent mutations in the MECP2 gene, including four nonsense mutations that truncate the protein.
Researchers in the Human Genetics Research lab are exploring the processes that regulate MeCP2 expression and function, the role of MeCP2 in neuronal and osteoblast function using both cell culture and model organism-based systems. We are also working to develop a new assay that can be used for high-throughput screening of new compounds that can restore function to mutant protein.
Autism and Chromosome 15 Duplications
Duplications of the proximal short arm of chromosome 15 lead to a complex syndrome that is associated with autism spectrum disorders, intellectual disabilities, seizures, and a risk for sudden death. The region that is duplicated is subject to genomic imprinting and thus displays parent-of-origin specific gene expression. We are currently studying the molecular characteristics of chromosome 15 duplications in a large patient cohort paired with detailed behavioral testing of the individuals.
It appears that the relationship between the molecular characteristics of the chromosome and the clinical outcome is complex, and investigators in the Human Genetics Research lab are working to determine the basis of the clinical variablility.