Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by mutations in the Fragile X mental retardation 1 (FMR1) gene. FXS is a leading monogenic cause of autism spectrum disorder and a frequent form of inherited intellectual disability. In most cases, the mutation is an expansion of a microsatellite (CGG triplet), which leads to suppression of the expression of the fragile X mental retardation protein (FMRP), an RNA-binding protein involved in multiple aspects of mRNA metabolism. In some cases, individuals with FXS carry a point mutation in FMR1. Interestingly, we found that the previously published Fmr1 knockout rat model of FXS expresses a transcript with an in-frame deletion of the KH1 domain. KH1 domains are RNA-binding domains and several of the few, known point mutations associated with FXS are found in the KH domains of FMR1. We observed that this deletion leads to medial prefrontal cortex (mPFC)-dependent attention deficits in both males and females, similar to those observed in individuals with FXS. Deletion of the KH1 domain also led to alterations in transcriptional profiles within the mPFC, which mapped to two weighted gene co-expression network analysis modules. We demonstrated that these modules are conserved in human frontal cortex, are enriched for known FMRP targets and for genes involved in neuronal and synaptic processes, and that one of the modules is enriched for genes that are implicated in autism, intellectual disability and schizophrenia. Hub genes in these conserved modules represent potential targets for FXS. These findings provide support for a prefrontal deficit in FXS and indicate that attentional testing might be a reliable cross-species tool for investigating the pathophysiology of FXS and a potential readout for pharmacotherapy testing and identify dysregulated gene expression modules in a relevant brain region.

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