A 3′ untranslated region variant in FMR1 eliminates neuronal activity-dependent translation of FMRP by disrupting binding of the RNA-binding protein HuR

Fragile X syndrome is a common cause of intellectual disability and autism spectrum disorder. The gene underlying the disorder, fragile X mental retardation 1 (FMR1), is silenced in most cases by a CGG-repeat expansion mutation in the 5' untranslated region (UTR). Recently, we identified a vari...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2015-11, Vol.112 (47), p.E6553-E6561
Main Authors: Suhl, Joshua A, Muddashetty, Ravi S, Anderson, Bart R, Ifrim, Marius F, Visootsak, Jeannie, Bassell, Gary J, Warren, Stephen T
Format: Article
Language:English
Subjects:
3' Untranslated Regions - genetics
Alleles
Animals
Autism
Base Sequence
Biological Sciences
Biotinylation
Cells, Cultured
Dendrites - metabolism
ELAV-Like Protein 1 - metabolism
Electrophoretic Mobility Shift Assay
Fragile X Mental Retardation Protein - genetics
Fragile X Mental Retardation Protein - metabolism
Genes, Reporter
Genetic Loci
Humans
Learning disabilities
Luciferases - metabolism
Male
Mice
Molecular Sequence Data
Mutation
Neurons - metabolism
PNAS Plus
Protein Binding
Protein Biosynthesis
Proteins
Receptors, Glutamate - metabolism
RNA Stability
RNA, Messenger - genetics
RNA, Messenger - metabolism
RNA-protein interactions
Rodents
Sequence Alignment
Signal Transduction - genetics
Synapses - metabolism
Tandem Mass Spectrometry
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Summary:Fragile X syndrome is a common cause of intellectual disability and autism spectrum disorder. The gene underlying the disorder, fragile X mental retardation 1 (FMR1), is silenced in most cases by a CGG-repeat expansion mutation in the 5' untranslated region (UTR). Recently, we identified a variant located in the 3'UTR of FMR1 enriched among developmentally delayed males with normal repeat lengths. A patient-derived cell line revealed reduced levels of endogenous fragile X mental retardation protein (FMRP), and a reporter containing a patient 3'UTR caused a decrease in expression. A control reporter expressed in cultured mouse cortical neurons showed an expected increase following synaptic stimulation that was absent when expressing the patient reporter, suggesting an impaired response to neuronal activity. Mobility-shift assays using a control RNA detected an RNA-protein interaction that is lost with the patient RNA, and HuR was subsequently identified as an associated protein. Cross-linking immunoprecipitation experiments identified the locus as an in vivo target of HuR, supporting our in vitro findings. These data suggest that the disrupted interaction of HuR impairs activity-dependent translation of FMRP, which may hinder synaptic plasticity in a clinically significant fashion.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1514260112