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

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.

The roles of RNA processing in translating genotype to phenotype

“…There are several examples of SNVs that create an upstream open reading frame within the 5′ UTR of an mRNA and affect translation efficiency of the encoded protein product 91,92 . An analysis in LCLs, which identified thousands of novel open reading frames, also identified more than 300 SNVs that influenced the ratio of translation at the alternative versus main open reading frames 93 .…”

Axonal ribosomes and mRNAs associate with fragile X granules in adult rodent and human brains

“…FMRP is an RNA binding protein that serves as a critical regulator of experience-dependent translation in neurons (8). Loss of FMRP perturbs experience-dependent plasticity and results in the autism-related disorder Fragile X syndrome (FXS) (8)(9)(10)(11)(12)(13). In addition to its role in the somatodendritic compartment, FMRP also associates with a distinct granule termed the FXG (Fragile X granule).…”

Altered Bioenergetics in Primary Dermal Fibroblasts from Adult Carriers of the FMR1 Premutation Before the Onset of the Neurodegenerative Disease Fragile X-Associated Tremor/Ataxia Syndrome

“…The full mutation is causative of the fragile X syndrome (FXS), the most common inherited form of mental retardation. The FMR1 mRNA is rapidly translated at synapses in an activity-dependent manner [1], where it constrains local synaptic protein translation [2]. FMRP, the protein product of FMR1 , critically regulates synaptic function, and its transcriptional loss leads to FXS [3], syndrome associated with a high co-morbidity with autism [4, 5].…”