Stephen T. Warren, Ph.D., FACMG
Department of Human Genetics
Dr. Warren is best known for his genetics research on intellectual disability (ID). It had been appreciated since the 1930s that cognitive impairment was more common in males than females, subsequently leading to the hypothesis that there are likely genes on the X chromosome (of which males have only one copy) that, when mutated, result in ID. In the 1960s it was discovered that rather than many genes on the X chromosome that are involved in ID, a single locus accounted for most X-linked ID and this disorder was later called fragile X syndrome. Dr. Warren organized and led an international group of collaborators that isolated the FMR1 gene responsible for this syndrome in 1991. The cloning of this locus also discovered, for the first time, a trinucleotide repeat expansion mutation, now known to be responsible for dozens of diseases. Dr. Warren subsequently demonstrated that the expanded FMRI repeat in patients leads to transcriptional suppression and the absence of the encoded protein, FMRP. He has shown that this protein is a selective RNA-binding protein and identified FMRP associated mRNAs. He has demonstrated that FMRP is involved in the regulation of local protein synthesis at the synapse and that in the absence of FMRP, the FMRP-associated mRNAs are over translated, in an activity-dependent manner. He has shown that this leads to enhanced AMPA receptor internalization and directly to weakened synaptic strength, likely the direct cause of the cognitive deficit in patients. This decades long investigation into this disorder has led to a theory that posits therapeutic approaches using mGluR antagonists and Dr. Warren recent completed a chemical library screen to rescue FMRP-deficient phenotypes and identified GABA agonists as additional candidate drugs. This work has now directly led to several ongoing clinical trials, here at Emory and elsewhere, of drugs of both classes to evaluate the therapeutic efficacy in fragile X syndrome.