Investigating the Neurogenetic Interactions in Fragile X Syndrome

Dr. Lee is investigating how the Fragile X protein (FMRP) regulates gene expression in the human brain by binding to specific messenger RNAs (mRNAs). Using enhanced crosslinking immunoprecipitation followed by sequencing (eCLIP-seq), the researcher will map the RNAs bound by FMRP across multiple human brain regions, developmental stages, and sexes. Early findings suggest that the FMRP–RNA interactome is highly dynamic, varying by brain region and age and showing important differences between male and female brains. These results may help explain why Fragile X syndrome presents with different symptoms and levels of severity across individuals.

A second component of the project focuses on genetic modifiers of seizures in Fragile X syndrome, a common and sometimes severe clinical feature of the disorder. By analyzing whole-genome sequencing data from Fragile X patients with and without seizures, the study has identified several candidate genes that may influence seizure risk. These genes will be tested experimentally using multiple model systems, including Drosophila models of Fragile X and human neurons derived from induced pluripotent stem cells (iPSCs), where neuronal activity can be measured directly.

Together, these complementary approaches aim to link molecular mechanisms to clinical outcomes in Fragile X syndrome. By identifying how FMRP regulates RNA networks in the brain and uncovering genes that modify Fragile X symptoms, the research could reveal new biological pathways involved in the disorder and point to novel therapeutic targets.