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The molecular biology of FMRP: new insights into fragile X syndrome

Nature Reviews Neuroscience volume 22, pages 209–222 (2021)Cite this article

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Abstract

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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Fig. 1: Brain cell types affected in fragile X syndrome.
Fig. 2: Functions of FMRP targets.
Fig. 3: Methods for the analysis of transcriptome-wide translation.
Fig. 4: Models of FMRP-mediated translational regulation.
Fig. 5: Regulation of nuclear functions by FMRP.
Fig. 6: Summary of FMRP’s activities.

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Acknowledgements

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.

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  1. Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA

    Joel D. Richter

  2. Waisman Center, University of Wisconsin-Madison, Madison, WI, USA

    Xinyu Zhao

  3. Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA

    Xinyu Zhao

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The authors contributed equally to all aspects of the article.

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Correspondence to Joel D. Richter or Xinyu Zhao.

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Nature Reviews Neuroscience thanks B. Bardoni; R. Kelleher; E. Schuman; and N. Sonenberg, who co-reviewed with I. Gantois, for their contribution to the peer review of this work.

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Glossary

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.

Topoisomerase

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 22, 209–222 (2021). https://doi.org/10.1038/s41583-021-00432-0

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