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Proc Natl Acad Sci U S A. 2015 Nov 24;112(47):E6553-61. doi: 10.1073/pnas.1514260112. Epub 2015 Nov 9.

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

Author information

1
Department of Human Genetics, Emory University, Atlanta, GA 30322;
2
Department of Cell Biology, Emory University, Atlanta, GA 30322;
3
Department of Human Genetics, Emory University, Atlanta, GA 30322; Department of Cell Biology, Emory University, Atlanta, GA 30322;
4
Department of Human Genetics, Emory University, Atlanta, GA 30322; Department of Biochemistry, Emory University, Atlanta, GA 30322; Department of Pediatrics, Emory University, Atlanta, GA 30322 swarren@emory.edu.

Abstract

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.

KEYWORDS:

FMR1; FMRP; HuR; autism; fragile X syndrome

PMID:
26554012
PMCID:
PMC4664359
DOI:
10.1073/pnas.1514260112
[Indexed for MEDLINE]
Free PMC Article

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