Affordable Access

deepdyve-link
Publisher Website

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

Authors
  • Suhl, Joshua A1
  • Muddashetty, Ravi S2
  • Anderson, Bart R3
  • Ifrim, Marius F2
  • Visootsak, Jeannie1
  • Bassell, Gary J2
  • Warren, Stephen T4
  • 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 [email protected]
Type
Published Article
Journal
Proceedings of the National Academy of Sciences
Publisher
Proceedings of the National Academy of Sciences
Publication Date
Nov 24, 2015
Volume
112
Issue
47
Identifiers
DOI: 10.1073/pnas.1514260112
PMID: 26554012
Source
Medline
Keywords
License
Unknown

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.

Report this publication

Statistics

Seen <100 times