FXS is the most common single-gene disorder responsible for intellectual disability. Most patients inherit the syndrome through a maternal repeat expansion mutation that silences the FMR1 gene and results in loss of FMRP. Loss of fragile X mental retardation protein 1 (FMRP) causes a wide range of abnormalities. Here, we demonstrate an independent presynaptic function for FMRP through the study of an ID patient with an FMR1 missense mutation.
Firstly, analysis of previous sequencing data of 963 developmentally delayed males, we identified a patient with an R138Q missense mutation in the FMR1 gene without the CGG-repeat expansion. R138Q-FMRP is robustly present in polyribosome fractions.
Next, postsynaptic AMPA receptor trafficking is influenced by FMRP-mediated control of local protein synthesis. R138Q-FMRP was able to regulate normal AMPA receptor trafficking, as well as retaining normal polyribosome association and mRNA binding functions.
Finally, The R138Q mutation also disrupts FMRP’s interaction with the large-conductance calcium-activated potassium (BK) channels that modulate AP width, particularly with the BK β4-subunit. FMRP have also been linked to neuronal and circuit hyper excitability in FXS animal models.
In the future, it is interesting to target BK channels as a useful component of FXS therapy.