FXS causing missense mutations disrupt FMRP granule formation, dynamics, and function.

Emily L Starke,Scott A Barbee,Keelan Zius,Gregory P Copenhaver

doi:10.1371/journal.pgen.1010084

Abstract

Fragile X Syndrome (FXS) is the most prevalent cause of inherited mental deficiency and is the most common monogenetic cause of autism spectral disorder (ASD). Here, we demonstrate that disease-causing missense mutations in the conserved K homology (KH) RNA binding domains (RBDs) of FMRP cause defects in its ability to form RNA transport granules in neurons. Using molecular, genetic, and imaging approaches in the Drosophila FXS model system, we show that the KH1 and KH2 domains of FMRP regulate distinct aspects of neuronal FMRP granule formation, dynamics, and transport. Furthermore, mutations in the KH domains disrupt translational repression in cells and the localization of known FMRP target mRNAs in neurons. These results suggest that the KH domains play an essential role in neuronal FMRP granule formation and function which may be linked to the molecular pathogenesis of FXS.

Highlights

Fragile X Syndrome (FXS) is the most common cause of inherited intellectual disability in humans [1]
Advances in high-throughput sequencing technologies have led to the discovery of patients with severe FXS caused by single mutations in important regions of the Fragile X Mental Retardation Protein (FMRP) protein
Using a well-characterized FXS model system, we have found that two disease-causing mutations in FMRP disrupt the formation, dynamics, and function of RNA- and protein-containing granules in neurons

Summary

Introduction

Fragile X Syndrome (FXS) is the most common cause of inherited intellectual disability in humans [1]. FXS is caused by epigenetic silencing of the FMR1 gene due to a long CGG repeat expansion in the 5’UTR, resulting in hypermethylation of the FMR1 locus and subsequent transcriptional silencing [2]. This results in loss of expression of the encoded Fragile X Mental Retardation Protein (FMRP), an evolutionarily conserved RNA-binding protein (RBP) that binds to many mRNAs in the mammalian brain. FMRP-containing RNA transport granules (hereafter called “FMRP granules”) are actively transported in both axons and dendrites [5,6,7,8] These granules carry translationally repressed mRNAs to synapses where they are derepressed in response to synaptic activity. Local translation of critical mRNAs is essential for long-term synaptic plasticity and is defective in FXS [9]

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