Most patients inherit the syndrome through a maternal repeat expansion mutation that transcriptionally silences the FMR1 gene and results in loss of the gene product, FMRP. Here, we demonstrate an independent presynaptic function for FMRP through the study of an ID patient with an FMR1 missense mutation.

After sequencing 963 developmentally delayed males, we identified a patient with an R138Q missense mutation in the FMR1 gene.

The R138Q mutation does not impair FMRP’s postsynaptic function as a translation regulator, as evidenced by rescue of AMPA receptor trafficking, intact polyribosome association, and mRNA pull-down.  Expression of the mutant FMRP is unable to rescue structural defects at the neuro-muscular junction in fragile x mental retardation 1 deficient Drosophila.

We show that R138Q is a partial loss-of-function mutation that specifically impairs a presynaptic FMRP function while preserving the translation regulation capabilities of FMRP. Besides, the R138Q mutation also disrupts FMRP’s interaction with the large-conductance calcium-activated potassium (BK) channels that modulate AP width.

In summary, our study of the R138Q missense mutation in FMR1 provides a first step in opening the door of the domain-specific functions of FMRP in pre- and postsynaptic compartments, and their contribution to various elements of FXS pathophysiology.