Fragile X Syndrome (FXS) is one of the most common inherited causes of intellectual disability and autism1. In the vast majority of cases, this X-linked disorder is caused by expansions of a CGG repeat in the 5’ untranslated region of the FMR1 gene. The most common normal allele has 30 CGG-repeats while FXS alleles have over 200 repeats. These latter alleles are called “full mutations” to distinguish them from another allelic class called “premutations” (55 – 200 repeats) that are found among carriers of FXS. Full mutations trigger an epigenetic silencing of the FMR1 gene and consequently the absence of it encoded protein, FMRP. Thus FXS is functionally due to a null mutation.
Considerable research ensued over the past 20 years deciphering the normal function of FMRP and the consequence of its absence. Today, FXS is considered to be one the best understood neuropsychiatric diseases. Briefly, we now know that FMRP is abundant in neurons and present in dendritic spines where it is believed to play a key role in synaptic plasticity. FMRP is an RNA-binding protein the associates with a small subset of mRNAs and regulates their translation, utilizing microRNAs and the RISC complex. FMRP is a phosphoprotein and when phosphorylated represses local translation of bound mRNAs and, following excitatory synaptic activity (particularly mGluR5 mediated), is quickly dephosphorylated producing an immediate bolus of newly synthesized proteins. Presumably one or more of the newly synthesized proteins triggers AMPA receptor trafficking, modulating synaptic strength.
In the absence of FMRP, this regulation of local protein synthesis is lost and those mRNAs normally regulated by FMRP are constitutively translated, leading to their over abundance in the dendritic spine. Consequently, excessive internalization of the AMPA receptor occurs leading to enhanced LTD and weakened synaptic strength; the likely cause of the cognitive deficit in patients. Thus, in the absence of the negative influence of FMRP on translation, it would appear as if there is an exaggerated response to mGluR stimulation. This led to the hypothesis that mGluR5 antagonists might reverse FXS-like phenotypes in model systems. Indeed, many laboratories have shown, using mouse, Drosophila, and neuron cultures, that such antagonists reverse most abnormal phenotypes due to FMRP deficiency. Encouraged by these results, our group performed a chemical library screen for additional compounds that could rescue dfmp-deficient phenotypes in the Drosophila model and identified GABA agonists as also able to restore normal phenotype by inhibiting the exaggerated excitatory pathway. Both classes of drugs are now in phase II/III clinical trials at several sites throughout the world.Our current studies are examining the precise mechanisms by which FMRP is controlled by phosphorylation and involve development of knock-in mice with phosphomimic amino acid changes at serine 499. We are also following up on conventional mutations we have identified in patients referred to us to rule out fragile X syndrome but did not have repeat expansion. Some missense mutations are exciting in what they may reveal about FMRP function as well as clinical correlations. We are exploring a newly discovered nuclear function of FMRP as well as developing induced puripotent stem cells from patients.