PT - JOURNAL ARTICLE AU - Carla E. M. Golden AU - Michael S. Breen AU - Lacin Koro AU - Sankalp Sonar AU - Kristi Niblo AU - Andrew Browne AU - Daniele Di Marino AU - Silvia De Rubeis AU - Mark G. Baxter AU - Joseph D. Buxbaum AU - Hala Harony-Nicolas TI - Disruption of the KH1 domain of <em>Fmr1</em> leads to transcriptional alterations and attentional deficits in rats AID - 10.1101/338988 DP - 2018 Jan 01 TA - bioRxiv PG - 338988 4099 - http://biorxiv.org/content/early/2018/06/09/338988.short 4100 - http://biorxiv.org/content/early/2018/06/09/338988.full AB - Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by mutations in the FMR1 gene. FXS is a leading monogenic cause of autism spectrum disorder (ASD) and inherited intellectual disability (ID). In most cases, the mutation is an expansion of a microsatellite (CGG triplet), which leads to suppressed expression of the fragile X mental retardation protein (FMRP), an RNA-binding protein involved in multiple aspects of mRNA metabolism. Interestingly, we found that the previously published Fmr1 knockout rat model of FXS expresses a transcript with an in-frame deletion of a K-homology (KH) domain, KH1. KH domains are RNA-binding domains of FMR1 and several of the few, known point mutations associated with FXS are found within them. We observed that this deletion leads to medial prefrontal cortex (mPFC)-dependent attention deficits, similar to those observed in FXS, and to alterations in transcriptional profiles within the mPFC, which mapped to two weighted gene coexpression 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 is enriched for genes that are implicated in ASD, ID, and schizophrenia. Hub genes in these conserved modules represent potential targets for FXS. These findings provide support for a prefrontal deficit in FXS, 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.Significance Statement The significance of the current study lies in two key domains. First, this study demonstrates that deletion of the Fmrp-KH1 domain is sufficient to cause major mPFC-dependent attention deficits in both males and females, like those observed in both individuals with FXS and in knockout mouse models for FXS. Second, the study shows that deletion of the KH1 domain leads to alterations in the transcriptional profiles within the medial prefrontal cortex (mPFC), which are of potential translational value for subjects with FXS. These findings 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 also highlight hub genes for follow up.AcknowledgementsThis work was supported by the Seaver Foundation (to JDB, HHN, SDR, CEMG, and MSB), Autism Speaks (to JDB), Autism Science Foundation Grant No. 17-001 (to MSB), and the grant F31 MH115656-01 (to CEMG). Carla E. M. Golden is a Seaver Graduate Fellow and Michael S. Breen is a Seaver Postdoctoral Fellow. We thank Eilam Doron, who contributed to this work.