Fmr1 translationally activates stress-sensitive mRNAs encoding large proteins in oocytes and neurons

Mutations in Fmr1 are the leading heritable cause of intellectual disability and autism spectrum disorder. We previously found that Fmr1 acts as a ~2-fold activator of translation of large proteins in Drosophila oocytes, in contrast to its proposed role as a repressor of translation elongation. Here, we show that genes associated with autism spectrum disorders tend to be dosage-sensitive and encode proteins that are larger than average. Reanalysis of Fmr1 KO mouse cortex ribosome profiling data demonstrates that autism-associated mRNAs encoding large proteins exhibit a concordant reduction in ribosome footprints, consistent with a general role for Fmr1 as a translational activator. We find no evidence that differential ribosomal pausing affects translational output in Fmr1-deficient Drosophila oocytes or mouse cortex. Furthermore, long Fmr1 target transcripts are preferentially enriched in stress granules upon acute stress. Our data thus identify a critical role for Fmr1 in promoting the translation of long, stress-sensitive, autism-associated mRNAs.