A 3‧ untranslated region variant in FMR1 eliminates neuronal activity-dependent translation of FMRP by disrupting binding of the RNA-binding protein HuR

The fragile X mental retardation protein (FMRP) is most highly expressed in neurons, and is critical for proper synaptic functioning. Fragile X syndrome, a common cause of intellectual disability, is the result of absent or dysfunctional FMRP, highlighting its importance to the processes underlying learning and memory. A rapid upregulation of FMRP synthesis at the synapse in response to specific neuronal signals is a key step in maintaining a dynamic synapse, although the mechanisms governing this up-regulation are not well-understood. We show that a variant in the 3'UTR of fragile X mental retardation 1 (FMR1) causes the loss of this characteristic increase in synaptic FMRP synthesis, which may lead to developmental delay in patients. These data identify several mechanisms and molecules modulating activity-dependent translation of FMRP.