Fragile X mental retardation protein (FMRP) is the product of the fragile X mental retardation 1 gene (FMR1), a gene that — when epigenetically inactivated by a triplet nucleotide repeat expansion — causes the neurodevelopmental disorder fragile X syndrome (FXS). FMRP is a widely expressed RNA-binding protein with activity that is essential for proper synaptic plasticity and architecture, aspects of neural function that are known to go awry in FXS. Although the neurophysiology of FXS has been described in remarkable detail, research focusing on the molecular biology of FMRP has only scratched the surface. For more than two decades, FMRP has been well established as a translational repressor; however, recent whole transcriptome and translatome analyses in mouse and human models of FXS have shown that FMRP is involved in the regulation of nearly all aspects of gene expression. The emerging mechanistic details of the mechanisms by which FMRP regulates gene expression may offer ways to design new therapies for FXS.
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Work in the authors’ laboratories was supported by the NIH (U54HD082013, GM046779 and GM135087 to J.D.R., R01MH116582, MH118827 and R01NS105200 to X.Z and U54HD090256 to the Waisman Center), the Simons Foundation (to J.D.R.) and a Jenni and Kyle Professorship to X.Z.
The authors declare no competing interests.
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- RNA-binding protein
Member of a family of proteins that frequently contain certain amino acid sequence motifs that have a strong avidity for single-stranded or double-stranded RNA.
- Human pluripotent stem cells
Cells that have the capability to differentiate into any cell of the body.
- Gene editing
Alteration (by insertion, deletion or substitution) of the nucleotide sequence within a gene, frequently by way of CRISPR–Cas9 technology.
- mRNA splicing
The process by which precursor RNA is processed into mature RNA through removal of intron-derived sequences.
- Next-generation sequencing
Massively parallel and ultra-high-throughput sequencing.
- Gene network analysis
Analysis of gene involvement in two or more processes, which in turn may contain many genes that contribute to a given process.
- mRNA codon bias
A situation where an mRNA does not contain all codons for a given amino acid in equal proportions.
- N 6-Methyladenosine
(m6A). Adenosine methylated at the nitrogen at the 6 position.
- Phase separation
Physical state of a protein that can form a membraneless separation between liquid and gel-like phases.
- Secondary structures
In RNA, intramolecular base pairing.
- Network-based integrative analysis
A process that seeks to integrate differential gene expression patterns based on calculated probability values with network-based meta-analysis to identify patterns of genes and pathways that may be impacted by underlying biological conditions such as disease.
An enzyme that unwinds DNA.
- Ribosome translocation
The movement of a ribosome in the 5′ to 3′ direction as it translates mRNA sequence information into a polypeptide.
- Stress granule
A membraneless subcellular organelle that forms in response to cellular stress and contains a variety of RNAs and proteins.
- DNA damage response
The response of cells to identify and repair broken DNA strands.
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Richter, J.D., Zhao, X. The molecular biology of FMRP: new insights into fragile X syndrome. Nat Rev Neurosci (2021). https://doi.org/10.1038/s41583-021-00432-0