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Cited by 29Genetics and Neurodevelopmental DisordersAutism Spectrum Disorder ResearchWilliams Syndrome Research

Deletion of the KH1 Domain of Fmr1 Leads to Transcriptional Alterations and Attentional Deficits in Rats

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Golden, Carla E M, Breen, Michael S, Koro, Lacin, Sonar, Sankalp, Niblo, Kristi, Browne, Andrew, Burlant, Natalie, Di Marino, Daniele +4 more·2019·Cerebral Cortex
DOI 10.1093/cercor/bhz029PMC PMC6458915

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Abstract

Abstract 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.

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  • The deletion of exon 8 in the Fmr1-Δexon 8 rat is sufficient to cause FXS-like traits, such as deficits in sustained visuospatial attention, altered patterns of social interaction, cognitive impairment, and abnormal synaptic plasticity.

    “Such deletion is sufficient to cause FXS-like traits, such as deficits in sustained visuospatial attention [34], altered patterns of social interaction, and cognitive impairment [28], together with abnormal synaptic plasticity [32,35,36].”

    From Brain Cholesterol Biosynthetic Pathway Is Altered in a Preclinical Model of Fragile X Syndrome (2022) · cites this paper as [34]

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Authors
Golden, C. E. M., Breen, M. S., Koro, L., Sonar, S., Niblo, K., Browne, A., Burlant, N., Di Marino, D., De Rubeis, S., Baxter, M. G., Buxbaum, J. D., & Harony-Nicolas, H.
Affiliations
  • Icahn School of Medicine at Mount Sinai (US)
  • Faculty of Biomedical Sciences, Institute of Computational Science, Center for Computational Medicine in Cardiology, Università della Svizzera Italiana (USI), Lugano, Switzerland
  • Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Corresponding author
Buxbaum, Joseph D
ORCID
Venue
Cerebral Cortex
Publisher
Oxford University Press (OUP)
Published
2019-03-16
Volume
29
Issue
5
Pages
2228-2244
ISSN
  • 1047-3211 (ISSN-L)
  • 1460-2199
DOI
10.1093/cercor/bhz029
PMC
PMC6458915
OpenAlex
W2950095747
Cited by
29
References
21
Citations by year
2026: 4 · 2025: 3 · 2024: 4 · 2022: 6 · 2021: 4 · 2020: 6 · 2019: 1 · 2017: 1
FWCI
2.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Cerebral Cortex (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion)
Funders
  • Autism Speaks
  • National Institutes of Health (1r01mh101584-01a1)
  • National Institute of Mental Health (R01-MH101584, F31MH115656)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Neuroscience › Developmental Neuroscience › Williams Syndrome Research
Keywords
fragile X syndrome, FMR1 gene, FMRP, exon 8 deletion, attention deficits, gene expression changes, medial prefrontal cortex, gene co-expression network, hub genes, therapeutic target, CGG repeat expansion, autism spectrum disorder
MeSH terms
Animals, Attention, Attention Deficit Disorder with Hyperactivity, Disease Models, Animal, Female, Fragile X Syndrome, Gene Expression Regulation, Male, Rats, Sprague-Dawley, Prefrontal Cortex, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1, Gene Regulatory Networks, Rats, Transgenic

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